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The 42nd David A. Karnofsky Memorial Award Lecture: Understanding Herbert M. Pinedo From VU University Medical Center, Amsterdam, the Netherlands. Published online ahead of print at www.jco.org on January 5, 2015. Presented at the 50th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2014. The treatments presented in this article represent personal choices made by the author in individual patients and do not necessarily reflect recommendations of evidence-based guidelines. Author’s disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Herbert M. Pinedo, MD, PhD, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3305w-510w/$20.00 DOI: 10.1200/JCO.2014.59.4036
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INTRODUCTION
The Dutch philosopher Baruch Spinoza (1632 to 1677) taught us in the 17th century that “there is no method without a preexisting idea.” Apart from inspiring me throughout my career, Spinoza has been a central figure in my life and the work I conducted for the largest part of my career at the VU University Medical Center (VUMC) in Amsterdam. In Spinoza, my family background and the city of Amsterdam come together. My ancestors and Spinoza lived not far apart on the same street, Houtgracht, in ancient Amsterdam. Quite recently, I discovered that my mother was a direct descendent of Spinoza. I am therefore proud of my background and the NWO (Netherlands Organisation for Scientific Research) Spinoza Prize, which I received in 1997 in recognition of our translational cancer research at the VUMC in Amsterdam. Translational research has been the focal point of our research endeavors over the past decades and continues to be so. Translational research means establishing a bridge between basic research and clinical oncology and crossing that bridge— back and forth—with the aim of taking diagnostics and treatment from bench to bedside, and vice versa. Translational research is geared toward understanding at the molecular level the cellular changes occurring in our patients. Therefore, we need to study the patient’s blood, other body fluids, tumor fluids, liquid biopsies (circulating tumor cells and DNA), and tissues in the laboratory, in a multidisciplinary patient-centered approach. In doing so, we have to stay open minded and observant, and allow ourselves to be triggered by unexpected findings that call for further investigation, and be ready to move away from rigid guidelines if our results so dictate, on the way to truly personalized medicine. In this article, I will review some of our achievements in five domains of cancer research and management of patients with cancer to illustrate how translational research may contribute to our understanding of the patient, the disease, and the treatment. I will present a number of individual patients from whom we have learned a lot, who have taught us precious lessons and led us to
formulate new working hypotheses to be tested in future studies. “Each patient is a pearl”; we should treat each patient as a pearl using our translational research capabilities. DRUG RESISTANCE
The first pearl is a patient with colorectal cancer (CRC) who taught us about drug resistance and the lack of evidence for P-glycoprotein pump (Pgp; MDR-1) blockade (Fig 1).1 This patient with stage III colon cancer, a 36-year old man, who was a manager at an oil company, had undergone left hemicolectomy and had started adjuvant chemotherapy in 1993. Soon thereafter, he developed para-aortic and supraclavicular lymph node metastases. He was entered in a phase II study of vinblastine plus bepridil, which was based on the lack of efficacy of natural products in CRC, reports indicating MDR-1 positivity of CRC, and the discovery that the calcium channel blocker bepridil is able to reverse MDR-1 resistance to doxorubicin in A2780 ovarian cancer cells in vitro in a concentration-dependent manner.2 Our patient responded to the combination of vinblastine and bepridil with a complete response (CR).3,4 A subsequent RNAse protection assay on a biopsy demonstrated that the tumor was Pgp positive. However, a further detailed analysis using immunohistochemistry showed that the Pgp-positive cells were macrophages, whereas the colon cancer cells in the lymph node were Pgp negative. Our conclusion was that the patient’s response was not based on blockade of Pgp, but instead on the exceptional sensitivity of this patient’s CRC to vinblastine. Eight months later, the patient had a relapse of the supraclavicular clone only. On the basis of the translational findings, it was decided to retreat him with vinblastine, but without bepridil this time. After two cycles of chemotherapy, he had a second clinical CR. Because this second CR was likely temporary again, the patient received involved-field radiotherapy after 17 cycles of chemotherapy. In 2006, he underwent total colectomy for a second primary. Today, he is still in continuous complete remission, 21 years after the start of treatment of his metastases, and he still manages the oil company.
© 2015 by American Society of Clinical Oncology
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
Agents that reverse the MDR phenotype (eg, verapamil, cyclosporine) P-glycoprotein pump
1
Inhibitors Endogenous substrates (eg, cortisol)
Passive diffusion
3
Fig 1. P-glycoprotein pump (MDR-1). Data adapted.1 MDR, multidrug resistance.
4 2 5
Nucleus
The outcomes of this patient support the theory of multiple tumor clones with differential sensitivity to specific treatments, in this case chemotherapy. Radiotherapy was required to eliminate the clone causing the supraclavicular metastasis. It also tells us that we cannot always rely on a single molecular laboratory test, in this case the RNAse protection, as the basis for our clinical decision making, and that we may have to treat patients unconventionally when faced with a tumor clone with lower sensitivity. The clinical and translational research findings in this patient, the fact that the remaining patients in our phase II study failed to respond, and the negative studies reported by others led us to abandon Pgp-based experimental treatment and MDR1 research at our institute.1 The next pearl I wish to present is a group of 10 patients with locally advanced breast cancer who were treated with a combination of doxorubicin (100 mg/m2) and cyclophosphamide (1,000 mg/m2) and were biopsied 2 or 24 hours after administration of the first dose of doxorubicin. Fluorescence microscopy showed that doxorubicin had not entered tumor cells in the biopsies of two patients, but only the stroma, and that the time between drug administration and biopsy did not affect this pattern,5 supporting the notion of a dose-response relationship. A possible way to overcome this type of pharmacodynamic drug resistance is by increasing drug concentration in the extracellular compartment, for instance, by applying the drug locally instead of systemically, provided the drug does not require metabolic activation in the liver. The latter applies to cisplatin. Cell-line data generated in our laboratory indicated that increasing extracellular drug concentrations are associated with increasing antitumor activity of cisplatin.6 In ovarwww.jco.org
ian cancer, intraperitoneal drug administration may be used to increase local drug exposure in an extreme manner. More recently, Alberts et al7 extensively reviewed the pros and cons of intraperitoneal platinum drugs in ovarian cancer.8,9 Their meta-analysis strongly supports the incorporation of an intraperitoneal cisplatin regimen to improve survival in the first-line treatment of stage III, optimally debulked ovarian cancer. The pooled hazard ratios for progressionfree and overall survival of intraperitoneal cisplatin, as compared with intravenous treatment regimens, were 0.792 (P ⫽ .001) and 0.799 (P ⬍ .001), respectively.9 Another series of preclinical experiments conducted at the Netherlands Cancer Institute by one of our PhD students demonstrated an advantage of using hyperthermia to increase the platinum drug exposure of peritoneal tumors.10-12 Increasing local drug concentration by intraperitoneal administration in combination with hyperthermia is therefore attempted as a way to overcome platinum drug resistance. Unfortunately, the application of hyperthermia in the clinical setting poses an additional logistic challenge over the already complex intraperitoneal drug administration. Nevertheless, the promising results with intraperitoneal platinum, combined with hyperthermia, have led to a multicenter phase III randomized clinical trial in the Netherlands for stage III ovarian carcinoma, randomly assigning patients to secondary debulking surgery with or without hyperthermic intraperitoneal chemotherapy—the OVHIPEC (Ovarian Cancer Hyperthermic Intraperitoneal Chemotherapy) study (ClinicalTrials.gov identifier NCT00426257). The trial, which is led by Dr van Driel of the Netherlands Cancer Institute in Amsterdam, is nearing completion of accrual. © 2015 by American Society of Clinical Oncology
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Activation of coagulation cascade Increased TAT complexes
Angiogenesis EC proliferation Hyperpermeability
Vascular homeostasis
lmmunomodulation
Kidney function
Fig 2. Multiple biologic effects of vascular endothelial growth factor (VEGF). Data adapted.13 EC, endothelial cell; TAT, thrombin-antithrombin.
Bone marrow function Blood pressure
VEGF Thyroid function
ANGIOGENESIS
1,600
Platelets (× 109/L)
700 VEGF Platelets
600
1,400 1,200
500
1,000
400
800
300
600
200
400
100
200
Serum VEGF (pg/mL)
Vascular endothelial growth factor (VEGF) has multiple biologic activities (Fig 2).13 I will discuss two roles of VEGF in particular: that is, activation of the coagulation cascade resulting in enhanced formation of thrombin-antithrombin (TAT) complexes and many other coagulation factors (eg, tissue factor, Von Willebrand factor), stimulation of angiogenesis through endothelial cell proliferation and induction of hyperpermeability, and the interplay between platelets and VEGF in tumor angiogenesis.14-17 I made an intriguing observation in a patient with locally advanced breast cancer receiving doxorubicin plus cyclophosphamide. I noticed a striking synchronization of platelet count and serum VEGF, from which we concluded that platelets are carriers of VEGF and that chemotherapy affects the status of the platelet-VEGF system (Fig 3). In a phase I study, we found that the addition of semaxanib (SU5416), an inhibitor of VEGF receptor tyrosine kinase, to cisplatin-gemcitabine chemotherapy in patients with non–small-cell lung cancer increased intravascular coagulation, as evidenced by an increase in the level of TAT complexes and several other coagulation factors, compared with chemotherapy or semaxanib alone.18,19 These observations taught us that a thorough evaluation of coagulation is warranted each time a new VEGF inhibitor is evaluated in phase I. A 40-year-old patient with a soft tissue sarcoma who participated in our phase I study with semaxanib taught us a lesson about VEGF
0
0 0
3
6
9
13
Time (weeks) Fig 3. Synchronization of platelet count and serum vascular endothelial growth factor (VEGF) in patient receiving chemotherapy. 512
© 2015 by American Society of Clinical Oncology
and endothelial leakage. Before the start of treatment and while receiving treatment, this patient had massive fluid accumulation in the center of a tumor in the left upper abdomen. We decided to draw fluid from this lesion and collected 600 mL of fluid, which seemed to have a 450-fold increased VEGF concentration compared with plasma and a 63-fold increased level of TAT complexes. Intratumoral fluid leaking from the surrounding tumor tissue can therefore be considered a “VEGF bomb,” which may exert pronounced effects on angiogenesis, coagulation, and bleeding tendency, all at the same time, in patients treated with drugs affecting the VEGF signaling pathway. Subsequently, we collected intratumoral fluid from 12 patients with soft tissue sarcomas.17 This process of intratumoral leakage is known to occur in other tumor types as well, but to a lesser extent, as a result of leakage of fluid from the tumor tissue. It is more pronounced in soft tissue sarcoma because of the nature of the tissue, which promotes fluid accumulation, and because of the fact that this tumor type forms a pseudo capsule, which retains the fluid within the tumor.
EPIGENETICS
Our work on epigenetics dates back to the 1970s. During one of my trips to the US National Cancer Institute, the drug decitabine, also know as 5-aza-2=-deoxcytidine, was offered to me as an experimental agent for further development in Europe within the European Organisation for Research and Treatment of Cancer. Decitabine induces DNA hypomethylation through inhibition of the enzyme DNA methyltransferase and thereby inhibits gene function. After we had conducted preclinical xenograft evaluations, which demonstrated schedule dependency20 and preclinical toxicology through the New Drug Development Office, the drug entered a phase I study in solid tumors at the VUMC in 198321 and additional studies in leukemia and myelodysplastic syndromes as of 1985. These studies fuelled interest in the drug in other parts of the world, which contributed to its current status as an approved treatment option (Dacogen; Otsuka Pharmaceutical, Tokyo, Japan) in acute myeloid leukemia and myelodysplastic syndromes. Of interest, a patient with a melanoma in the left nose fold (melanoma according to a recent retrospective diagnostic procedure using stored tumor tissue [originally diagnosed as an undifferentiated carcinoma]) participated in our phase I study of decitabine. The facial lesion had been treated with radiotherapy 1 year earlier. Not only did JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
his facial lesion show a dramatic response within 3 months of the start of treatment with decitabine, there was also considerable shrinkage of an involved lymph node in his neck. The node, while it was shrinking, was surgically excised and diagnosed (also retrospectively) as a melanoma metastasis with extensive infiltration of CD8⫹ T cells. Subsequently, the node area was irradiated, resulting in a durable remission for 1 year while on continued treatment with decitabine, followed by progression of the facial lesion. The lesson we learned from this pearl is that we always have to remain open to the possibility of exceptional unexpected responses. In retrospect, looking at the extensive T-cell infiltration in the metastatic lesion, we can say that we should have continued decitabine treatment, because this drug also has an immunologic component to its action profile. My work in the field of DNA methylation is still continuing, although in a different area: screening and early diagnosis of malignancies. In collaboration with colleagues at Technical University Twente in the Netherlands, I am developing a “smart pill” that detects hypermethylation of promoter regions of genes related to tumorigenesis in the GI tract. This nanopill concept is quite straightforward: one swallows a pill-like object that analyses the fluids it passes through during its journey down the GI tract for epigenetic tumor markers. The fluid entering the nanopill passes through a microfluidic affinity filter consisting of microscopic silicon pillars, functionalized with proteins that bind (hyper)methylated DNA. Methylated DNA is bound to the filter, resulting in a sample that contains all (hyper)methylated DNA. The resulting single-stranded DNA interacts with a detector. We use DNA probes complementary to the genes that are clinically proven to be related to cancer when their promoters are hypermethylated. These probes hybridize with the single-stranded DNA from the filter, thereby inducing a signal, which indicates that the gene that corresponds to that specific probe was hypermethylated. The detector then sends a signal to the person’s smart phone, and he or she may take action (eg, request a colonoscopy or positron emission tomography [PET] scan, also looking for tumors of organs draining onto the GI tract). The concept is currently under development using urine as the source of (hyper)methylated gene promoters to detect recurrence of bladder cancer.22-24 To create a working smart pill for the early detection of GI malignancies, miniaturization of the technology will be essential.
PERSONALIZED MEDICINE
The term personalized medicine refers to the incorporation of the patient’s tumor-specific characteristics into clinical decision making. Targeted drug treatment based on individual features of growth factor signaling pathways in the patient’s tumor, such as clinically relevant mutations of one or more elements of a pathway, is one of the ways personalized medicine is practiced. Important points of attack for targeted therapies, particularly for tyrosine kinase inhibitors, are intracellular tyrosine kinases associated with a growth factor receptor or regulatory proteins further downstream in the signaling pathway. Mutations of the genes of these regulatory proteins may lead to constitutive activation of the signaling cascade, causing uncontrolled cell division and tumor progression. The presence of such mutations may be determined by means of sequencing of the kinase genes. Absence or presence of mutated kinases provides important information on which treatment decisions can be based. www.jco.org
A 58-year-old female painter presented with right-sided locally advanced breast cancer and positive axillary nodes. The tumor was estrogen receptor (ER) positive and human epidermal growth factor receptor 2 negative. She received six cycles of neoadjuvant chemotherapy before breast-saving tumor excision. Subsequently, she received radiotherapy and long-term hormonal therapy with anastrozole. After 6 years of anastrozole treatment, she developed a single metastasis in the left lung, and lobectomy was performed. The metastasis was indeed ER positive. Postoperatively, hormonal treatment was switched to tamoxifen. One year later, she developed bone metastases. A plausible explanation for ER resistance to hormonal therapy in breast cancer may be post-translational modifications, such as ER phosphorylation. According to the literature, at least three kinase-regulated pathways may lead to ER phosphorylation and thus resistance: the RAF, mammalian target of rapamycin (mTOR), and protein kinase A (PKA) pathways.25-27 To determine how to overcome the resistance to hormonal therapy in our patient, tissue lysate of the resected lung metastasis was subjected to the PamGene (‘s-Hertogenbosch, the Netherlands) kinase platform, an alternative for tumor profiling by full genomic sequencing, focusing on drug target and (resistance) pathway activities. This study, conducted by Ruijtenbeek et al at PamGene, yielded evidence that mTOR inhibition (by dactolisib [BEZ235], an enzymatic inhibitor of mTOR, mimicking the effect of the mTOR blocker everolimus) and PKA inhibition (by a PKA inhibitor peptide) might overcome phosphorylation-dependent hormone resistance in this patient, whereas RAS-RAF-MEK-Erk pathway inhibition and Akt inhibition would not (Fig 4). Therefore, it was decided to continue the treatment of our patient with the combination of the aromatase inhibitor exemestane and the approved mTOR inhibitor everolimus. This treatment was started fairly recently, and initial signs are favorable (ie, lowering of serum tumor marker). This is in line with the positive data (improved progression-free survival) reported by Baselga et al28 for the combination of aromatase and mTOR inhibition using the same drug combination in postmenopausal patients with hormone receptor– positive advanced breast cancer. Should our patient experience progression on the current combination, we still have the option of treating the patient with a PKA inhibitor. Molecular imaging is becoming an important tool in the development and application of personalized medicine. The VU University and VUMC are leading institutes in the field of radiopharmaceuticals and sophisticated radioimaging. I will briefly review the work conducted by Van Dongen et al in the field of immuno-PET imaging using the zirconium-89 (89Zr) –labeled anti– c-Met antibody DN30. Quantitative PET imaging of Met-expressing human cancer xenografts was demonstrated in nude mice using DN30.29 This antibody may therefore be useful as an imaging tool in patients as an alternative for biopsies, if frequent biopsies are not feasible, and as a tool to detect different tumor clones. Furthermore, c-Met expression has been demonstrated to be an important determinant of resistance to epidermal growth factor receptor (EGFR) inhibitors.30 An example of the clinical use of radiopharmaceuticals and PET imaging is provided by the work of Bahce et al31 comparing patients with non–small-cell lung cancer with wild-type EGFR and those with an EGFR exon-19 deletion to predict drug resistance. This deletion confers responsiveness to EGFR tyrosine kinase inhibitors. PET imaging using [18F]fluorodeoxyglucose did not distinguish these patients, whereas PET imaging using [11C]erlotinib clearly did (Fig 5). This © 2015 by American Society of Clinical Oncology
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AKT
PKA mTOR
Raf/MEK/ Erk
PKA inhibitor
MK-2206
P BEZ235 (Dactolisib)
ERα
Activity (%)
Hormone therapy
Sorafenib ERα Fig 4. Which drug should be added to an aromatase inhibitor in a patient with breast cancer developing estrogen receptor (ER) resistance? Results of PamGene kinase platform (reprinted with permission from R. Ruijtenbeek). mTOR, mammalian target of rapamycin; PKA, protein kinase A.
100
50
-9 -8 -7 -6 -5 -11 -10 -9 -8 -7
-6 -9 -8 -7 -6 -5
-10 -8 -7 -6
-5 -4
[Compound] (log M)
noninvasive procedure allows differentiation of drug-sensitive and drug-resistant patients before the treatment is actually given, thereby saving patients noneffective treatments.32 IMMUNOTHERAPY
The report by Rosenberg et al33 on autologous lymphokine-activated killer cells and interleukin-2 in patients with metastatic cancer published in 1985 triggered me to embark on translational immunotherapy research. Today, cancer immunotherapy continues to be an important research theme at the VUMC Cancer Center Amsterdam (CCA). Under the motto “use the primary to treat the patient,” we have successfully modulated the patient’s adaptive immune system, targeting it toward the patient’s own tumor cells to eradicate residual disease after local treatment.34-36 One of the first patients we treated with an autologous vaccine (AV) in this way was a 58-year-old Brazilian man with
Wild-type EGFR
EGFR exon 19 deletion
[18F]FDG
[11C]Erlotinib
Fig 5. Prediction of resistance to epidermal growth factor receptor (EGFR) inhibitors in non–small-cell lung cancer using positron emission tomography imaging (reprinted and adapted with permission31). FDG, fluorodeoxyglucose. 514
© 2015 by American Society of Clinical Oncology
S100-positive melanoma. After resection of eight lung metastases, we prepared an AV of his metastases. There were many aggregates of lymphoid cells in between the tumor tissue and dense infiltration by activated CD8⫹ T cells, resembling reactive lymph follicles (Fig 6). The vaccine was administered intradermally every 3 weeks for four cycles and then every 3 months for a total of 2 years. At 2 years, a new lung lesion appeared, which was resected, and AV was resumed and continued for another 2 years. The microscopic observation of intrametastatic follicles of CD3⫹, CD4⫹, and CD8⫹ lymphocytes in the patient’s postvaccination metastasis indicated the promise of immunologic efficacy of our AV procedure. After a treatment-free period, the patient developed progressive chemotherapy-resistant lymphoma. At age 63 years, he died. Stimulated by the findings in this patient, we conducted a phase II study of AV with Bacillus Calmette-Guérin as vaccine adjuvant in 81 patients with American Joint CC stage III to IV melanoma and at least one resectable metastasis.35 Whenever feasible, radical metastasectomy was performed. Intradermal AV was started 4 to 5 weeks postoperatively and continued at a frequency of once every 3 weeks. Five-year survival was 48% and 34% in patients with stage III and IV disease, respectively. The degree of delayed-type hypersensitivity correlated with survival. No evidence of disease after surgery and the presence of tumor-associated antigen–specific cells in the tumor were prognostic. Another important AV study we conducted was a randomized phase III study in patients with CRC, stage II or III, one of the earliest of its kind.36 AV plus Bacillus Calmette-Guérin was administered intradermally. According to a recent evaluation, 15-year recurrencefree survival in the vaccinated group was significantly greater than in the control group.37 The effect of long-term administration of granulocytemacrophage colony-stimulating factor (GM-CSF), in combination with conventional neoadjuvant chemotherapy, on dendritic cell JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
A
B
Fig 6. Intrametastatic lymphoid follicles in patient with melanoma. HE, hematoxylin and eosin.
CD3+
HE
C
D
CD4+
CD8+
activation and clinical end points was studied in patients with locally advanced breast cancer.38-40 GM-CSF was chosen for its immunostimulatory effects (eg, in vivo recruitment and activation of dendritic cells) to achieve in vivo vaccination on chemotherapy-induced tumor antigen release. The trial showed a high response rate and good 3-year disease-free and overall survival rates, which compared favorably with results of previous studies in locally advanced breast cancer.38 It was hypothesized that these encouraging results were related to the prolonged presence of the primary tumor and to the long-term administration of the immunostimulant in the presence of the primary tumor and the axillary lymph nodes. A more recent vaccination phase I study in metastatic castrateresistant prostate cancer examined the feasibility of using a vaccine
derived from two prostate tumor cell lines, transduced to express and release GM-CSF (allogeneic GVAX; Cell Genesys, South San Francisco, CA), in combination with the anti–CTLA-4 monoclonal antibody ipilimumab at dosages ranging from 0.3 to 5.0 mg/kg every 4 weeks.41 This study represented the first clinical study of combined tumor vaccination and immune checkpoint inhibition. Remarkable remissions based on prostate-specific antigen responses (confirmed in some cases by bone scans) were observed, particularly in the expansion cohort treated at the 3.0-mg/kg ipilimumab dose. One patient at this dose level had a complete prostate-specific antigen response. Hypophysitis was a frequent adverse effect at the higher ipilimumab dose levels (3.0 and 5.0 mg/kg), but it was highly treatable with hormone replacement therapy, after which the scheduled study treatment could
Table 1. Guidance of Tumor Vaccination by T-Cell Profiling in Blood, Tumor, and Lymph Nodes Study
Tumor Type
Disease Stage
Baars et al,35 Haanen et al43 Melanoma
Metastatic
de Weger et al,37 Turksma et al (submitted for publication) Pinedo et al,40 Van Cruijsen et al (manuscript in preparation) Santegoets et al44
Primary, stage II to III
Colorectal cancer
Treatment Excision metastases plus autologous tumor cell vaccination Surgery plus autologous tumor cell vaccination
Locally advanced Primary, stage III to IV Neoadjuvant breast cancer chemotherapy plus in vivo vaccination Prostate cancer Advanced, hormone Allogeneic GVAX resistant vaccination
Immunostimulant
Predictive Factors
BCG
Melanoma-specific TILs, but not circulating CD8⫹ T cells
BCG
MSI/MSS, CD8 T-cell infiltration
GM-CSF
Lymph node DC rates and activation pretreatment Treg cells
Ipilimumab
Teff-to-Treg ratio and CTLA-4–positive Th cells, high DCs, low MDSC frequency
Abbreviations: BCG, Bacillus Calmette-Guérin; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; MDSC, myeloid-derived suppressor cell; MSI, microsatellite instability; MSS, microsatellite stability; Teff, effector T cell; Th, T helper cell; TIL, tumor-infiltrating lymphocyte; Treg, regulatory T cell.
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be resumed. Hypophysitis is a commonly reported autoimmune effect of anti–CTLA-4 antibodies that is mediated by pituitary expression of CTLA-4.42 Our vaccination studies in four different tumor types, using AV or allogeneic GVAX and increasingly powerful immunostimulants, have demonstrated that T-cell profiling in blood, tumor, and lymph nodes can provide treatment guidance as predictive biomarkers (Table 1).35,37,40,43,44 I propose combining AV also with emerging powerful immunostimulants, such as the immune checkpoint modulators, targeting PD1 and PD-L1 and other new immune targets. Studies on T-cell profiling after anti-PD1 and other types of immunologic treatment are ongoing. VUMC CCA
Throughout my career at the VUMC, I have stressed the importance of translational cancer research to better understand what is happening in our patients and how their outcomes may be improved by conventional or, if indicated, unconventional treatment approaches. To facilitate translational research and promote cross pollination between the various disciplines involved, we created the VUMC CCA as an organizational entity focusing on translational research in the spirit REFERENCES 1. Pinedo HM, Giaccone G: P-glycoprotein: A marker of cancer-cell behavior. N Engl J Med 333: 1417-1419, 1995 2. Schuurhuis GJ, Broxterman HJ, van der Hoeven JJ, et al: Potentiation of doxorubicin cytotoxicity by the calcium antagonist bepridil in anthracycline-resistant and -sensitive cell lines: A comparison with verapamil. Cancer Chemother Pharmacol 20:285-290, 1987 3. Linn SC, Giaccone G, Pinedo HM: Complete remission of metastatic colorectal cancer: A pitfall in a multidrug resistance reversal trial. Lancet 343: 1648-1649, 1994 4. Linn SC, van Kalken CK, van Tellingen O, et al: Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. J Clin Oncol 12:812-819, 1994 5. Lankelma J, Dekker H, Luque FR, et al: Doxorubicin gradients in human breast cancer. Clin Cancer Res 5:1703-1707, 1999 6. Oldenburg J, Begg AC, van Vugt MJ, et al: Characterization of resistance mechanisms to cisdiamminedichloroplatinum(II) in three sublines of the CC531 colon adenocarcinoma cell line in vitro. Cancer Res 54:487-493, 1994 7. Alberts DS, Delforge A: Maximizing the delivery of intraperitoneal therapy while minimizing drug toxicity and maintaining quality of life. Semin Oncol 33:S8-S17, 2006 (suppl 12) 8. Hess LM, Alberts DS: The role of intraperitoneal therapy in advanced ovarian cancer. Oncology (Williston Park) 21:227-322, 2007 9. Hess LM, Benham-Hutchins M, Herzog TJ, et al: A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer. Int J Gynecol Cancer 17:561-570, 2007 10. Los G, Smals OA, van Vugt MJ, et al: A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity. Cancer Res 52:1252-1258, 1992 516
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of David Karnofsky. In 2006, all 15 research groups, which were scattered around the VU campus until that time, moved to the newly created CCA building, which is directly connected to the clinic building of the VUMC. Tissue samples, blood samples, and other bodily fluids taken in the clinic can be transferred to the laboratory immediately, and the results of the laboratory investigations go back to the clinic immediately. Clinicians are required to have worked in the laboratory for 1 to 2 years and to work in the laboratory for at least 1 day per week thereafter. Conversely, postdoctoral and PhD students are required to come to the clinic to actually see the clinicians at work there with the patients and nurses. In this way, the translational bridge will continue to be crossed in both directions, pushing the cancer field forward. To finish in the spirit of Baruch Spinoza, this will take us from pre-existent ideas to a deeper understanding that will ultimately benefit our patients. This is my most fervent wish.
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the author are available with this article at www.jco.org.
11. Los G, van Vugt MJ, den Engelse L, et al: Effects of temperature on the interaction of cisplatin and carboplatin with cellular DNA. Biochem Pharmacol 46:1229-1237, 1993 12. Los G, van Vugt MJ, Pinedo H: Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer 69:235-241, 1994 13. Verheul HM, Pinedo HM: Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475-485, 2007 14. Verheul HM, Hoekman K, Luykx-de Bakker S, et al: Platelet: Transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187-2190, 1997 15. Pinedo HM, Verheul HM, D’Amato RJ, et al: Involvement of platelets in tumor angiogenesis? Lancet 352:1775-1777, 1998 16. Verheul HM, Jorna AS, Hoekman K, et al: Vascular endothelial factor stimulated endothelial cells promote adhesion and activation of platelets. Blood 96:4216-4221, 2000 17. Verheul HM, Hoekman K, Lupu F, et al: Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin Cancer Res 6:166-171, 2000 18. Kuenen BC, Rosen L, Smit EF, et al: Dose finding and pharmacokinetic study of cisplatin, gemcitabine and SU5416 in patients with solid tumors. J Clin Oncol 20:1657-1667, 2002 19. Marx GM, Steer CB, Harper P, et al: Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: Time to take stock! J Clin Oncol 20:1446-1448, 2002 20. Braakhuis BJ, van Dongen GA, van Walsum M, et al: Preclinical antitumor activity of 5-aza-2=deoxycytidine against human and neck cancer xenografts. Invest New Drugs 6:299-304, 1988 21. Van Groeningen CJ, Leyva A, O’Brien AM, et al: Phase I and pharmacokinetic study of 5-aza-2=deoxycytidine (NSC 127716) in cancer patients. Cancer Res 46:4831-4836, 1986 22. Enokida H, Nakagawa M: Epigenetics in bladder cancer. Int J Clin Oncol 13:298-307, 2008
23. Hoffman AM, Cairns P: Epigenetics of kidney cancer and bladder cancer. Epigenomics 3:19-34, 2011 24. Sánchez-Carbayo M: Hypermethylation in bladder cancer: Biological pathways and translational applications. Tumour Biol 33:347-361, 2012 25. De Leeuw R, Neefjes J, Michalides R: A role for estrogen receptor phosphorylation in the resistance to tamoxifen. Int J Breast Cancer 2011: 232435, 2011 26. Thomas RS, Sarwar N, Phoenix F, et al: Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-␣ activity. J Mol Endocrinol 40:173-184, 2008 27. Tokunaga E, Hisamatsu Y, Tanaka K, et al: Molecular mechanisms regulating the hormone sensitivity of breast cancer. Cancer Sci [epub ahead of print on August 26, 2014] 28. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptorpositive advanced breast cancer. N Engl J Med 366:520-529, 2012 29. Perk LR, Stigter-van Walsum M, Visser GW, et al: Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30. Eur J Nucl Med Mol Imaging 35:1857-1867, 2008 30. Boccaccio C, Luraghi P, Comoglio PM: METmediated resistance to EGFR inhibitors: An old liaison rooted in colorectal cancer stem cells. Cancer Res 74:3647-3651, 2014 31. Bahce I, Smit EF, Lubberink M, et al: Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res 19:183-193, 2013 32. Poot AJ, Slobbe P, Hendrikse NH, et al: Imaging of TKI-target interactions for personalized cancer therapy. Clin Pharmacol Ther 93:239-241, 2013 33. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492, 1985 JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
34. Baars A, Buter J, Pinedo HM: Making use of the primary tumour. Bioessays 25:79-86, 2003 35. Baars A, Claessen AM, van den Eertwegh AJ, et al: Skin tests predict survival after autologous tumor cell vaccination in metastatic melanoma: Experience in 81 patients. Ann Oncol 11:965-970, 2000 36. Vermorken JB, Claessen AM, van Tinteren H, et al: Active specific immunotherapy for stage II and stage III human colon cancer: A randomised trial. Lancet 353:345-350, 1999 37. de Weger VA, Turksma AW, Voorham QJ, et al: Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin Cancer Res 18:882-889, 2012 38. Honkoop AH, Luykx-de Bakker SA, Hoekman K, et al: Prolonged neoadjuvant chemotherapy with
GM-CSF in locally advanced breast cancer. Oncologist 4:106-111, 1999 39. Luykx-de Bakker SA, Verheul HM, de Gruijl TD, et al: Prolonged neoadjuvant treatment in locally advanced tumours: A novel concept based on biological considerations. Ann Oncol 10:155160, 1999 40. Pinedo HM, Buter J, Luykx-de Bakker SA, et al: Extended neoadjuvant chemotherapy in locally advanced breast cancer combined with GM-CSF: Effect on tumour-draining lymph node dendritic cells. Eur J Cancer 39:1061-1067, 2003 41. Van den Eertwegh AJ, Versluis J, van den Berg HP, et al: Combined immunotherapy with granulocyte-macrophage colony-stimulating factortransduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-
resistant prostate cancer: A phase 1 dose-escalation trial. Lancet Oncol 13:509-517, 2012 42. Iwama S, De Remigis A, Callahan MK, et al: Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 6:230ra45, 2014 43. Haanen JB, Baars A, Gomez R, et al: Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 55: 451-458, 2006 44. Santegoets SJ, Stam AG, Lougheed SM, et al: T cell profiling reveals high CD4⫹CTLA-4⫹ T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother 62:245-256, 2013
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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The 42nd David A. Karnofsky Memorial Award Lecture: Understanding The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Herbert M. Pinedo Stock or Other Ownership: Jennerex, Gilde Healthcare Services, VitrOmics Healthcare Services, PamGene Consulting or Advisory Role: Spectrum Pharmaceuticals, VitrOmics Healthcare Services, PamGene, Gilde Healthcare Services, Bristol-Myers Squibb, sanofi-aventis Travel, Accommodations, Expenses: Bristol-Myers Squibb, Spectrum Pharmaceuticals
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JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
Acknowledgment I thank the many clinicians and scientists who contributed to the work described in this article, in particular the members of my staff over the years at the VU University Medical Center: Victor van Beusechem, Epie Boven, Henk Broxterman, Jan Buter, Fons van den Eertwegh, Winald Gerritsen, Giuseppe Giaccone, Cees van Groeningen, Tanja de Gruijl, Hidde Haisma, Klaas Hoekman, Bart Kuenen, Frank Kruyt, Jan Lankelma, Frits Peters, Rik Scheper, Gerrit Jan Schuurhuis, Jan Vermorken, Wim van der Vijgh, and Elsken van der Wall. I also thank Joke van Diemen and Marinus Lobbezoo for editorial and writing assistance.
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The 42nd David A. Karnofsky Memorial Award Lecture: Understanding Herbert M. Pinedo From VU University Medical Center, Amsterdam, the Netherlands. Published online ahead of print at www.jco.org on January 5, 2015. Presented at the 50th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2014. The treatments presented in this article represent personal choices made by the author in individual patients and do not necessarily reflect recommendations of evidence-based guidelines. Author’s disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Herbert M. Pinedo, MD, PhD, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3305w-510w/$20.00 DOI: 10.1200/JCO.2014.59.4036
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INTRODUCTION
The Dutch philosopher Baruch Spinoza (1632 to 1677) taught us in the 17th century that “there is no method without a preexisting idea.” Apart from inspiring me throughout my career, Spinoza has been a central figure in my life and the work I conducted for the largest part of my career at the VU University Medical Center (VUMC) in Amsterdam. In Spinoza, my family background and the city of Amsterdam come together. My ancestors and Spinoza lived not far apart on the same street, Houtgracht, in ancient Amsterdam. Quite recently, I discovered that my mother was a direct descendent of Spinoza. I am therefore proud of my background and the NWO (Netherlands Organisation for Scientific Research) Spinoza Prize, which I received in 1997 in recognition of our translational cancer research at the VUMC in Amsterdam. Translational research has been the focal point of our research endeavors over the past decades and continues to be so. Translational research means establishing a bridge between basic research and clinical oncology and crossing that bridge— back and forth—with the aim of taking diagnostics and treatment from bench to bedside, and vice versa. Translational research is geared toward understanding at the molecular level the cellular changes occurring in our patients. Therefore, we need to study the patient’s blood, other body fluids, tumor fluids, liquid biopsies (circulating tumor cells and DNA), and tissues in the laboratory, in a multidisciplinary patient-centered approach. In doing so, we have to stay open minded and observant, and allow ourselves to be triggered by unexpected findings that call for further investigation, and be ready to move away from rigid guidelines if our results so dictate, on the way to truly personalized medicine. In this article, I will review some of our achievements in five domains of cancer research and management of patients with cancer to illustrate how translational research may contribute to our understanding of the patient, the disease, and the treatment. I will present a number of individual patients from whom we have learned a lot, who have taught us precious lessons and led us to
formulate new working hypotheses to be tested in future studies. “Each patient is a pearl”; we should treat each patient as a pearl using our translational research capabilities. DRUG RESISTANCE
The first pearl is a patient with colorectal cancer (CRC) who taught us about drug resistance and the lack of evidence for P-glycoprotein pump (Pgp; MDR-1) blockade (Fig 1).1 This patient with stage III colon cancer, a 36-year old man, who was a manager at an oil company, had undergone left hemicolectomy and had started adjuvant chemotherapy in 1993. Soon thereafter, he developed para-aortic and supraclavicular lymph node metastases. He was entered in a phase II study of vinblastine plus bepridil, which was based on the lack of efficacy of natural products in CRC, reports indicating MDR-1 positivity of CRC, and the discovery that the calcium channel blocker bepridil is able to reverse MDR-1 resistance to doxorubicin in A2780 ovarian cancer cells in vitro in a concentration-dependent manner.2 Our patient responded to the combination of vinblastine and bepridil with a complete response (CR).3,4 A subsequent RNAse protection assay on a biopsy demonstrated that the tumor was Pgp positive. However, a further detailed analysis using immunohistochemistry showed that the Pgp-positive cells were macrophages, whereas the colon cancer cells in the lymph node were Pgp negative. Our conclusion was that the patient’s response was not based on blockade of Pgp, but instead on the exceptional sensitivity of this patient’s CRC to vinblastine. Eight months later, the patient had a relapse of the supraclavicular clone only. On the basis of the translational findings, it was decided to retreat him with vinblastine, but without bepridil this time. After two cycles of chemotherapy, he had a second clinical CR. Because this second CR was likely temporary again, the patient received involved-field radiotherapy after 17 cycles of chemotherapy. In 2006, he underwent total colectomy for a second primary. Today, he is still in continuous complete remission, 21 years after the start of treatment of his metastases, and he still manages the oil company.
© 2015 by American Society of Clinical Oncology
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
Agents that reverse the MDR phenotype (eg, verapamil, cyclosporine) P-glycoprotein pump
1
Inhibitors Endogenous substrates (eg, cortisol)
Passive diffusion
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Fig 1. P-glycoprotein pump (MDR-1). Data adapted.1 MDR, multidrug resistance.
4 2 5
Nucleus
The outcomes of this patient support the theory of multiple tumor clones with differential sensitivity to specific treatments, in this case chemotherapy. Radiotherapy was required to eliminate the clone causing the supraclavicular metastasis. It also tells us that we cannot always rely on a single molecular laboratory test, in this case the RNAse protection, as the basis for our clinical decision making, and that we may have to treat patients unconventionally when faced with a tumor clone with lower sensitivity. The clinical and translational research findings in this patient, the fact that the remaining patients in our phase II study failed to respond, and the negative studies reported by others led us to abandon Pgp-based experimental treatment and MDR1 research at our institute.1 The next pearl I wish to present is a group of 10 patients with locally advanced breast cancer who were treated with a combination of doxorubicin (100 mg/m2) and cyclophosphamide (1,000 mg/m2) and were biopsied 2 or 24 hours after administration of the first dose of doxorubicin. Fluorescence microscopy showed that doxorubicin had not entered tumor cells in the biopsies of two patients, but only the stroma, and that the time between drug administration and biopsy did not affect this pattern,5 supporting the notion of a dose-response relationship. A possible way to overcome this type of pharmacodynamic drug resistance is by increasing drug concentration in the extracellular compartment, for instance, by applying the drug locally instead of systemically, provided the drug does not require metabolic activation in the liver. The latter applies to cisplatin. Cell-line data generated in our laboratory indicated that increasing extracellular drug concentrations are associated with increasing antitumor activity of cisplatin.6 In ovarwww.jco.org
ian cancer, intraperitoneal drug administration may be used to increase local drug exposure in an extreme manner. More recently, Alberts et al7 extensively reviewed the pros and cons of intraperitoneal platinum drugs in ovarian cancer.8,9 Their meta-analysis strongly supports the incorporation of an intraperitoneal cisplatin regimen to improve survival in the first-line treatment of stage III, optimally debulked ovarian cancer. The pooled hazard ratios for progressionfree and overall survival of intraperitoneal cisplatin, as compared with intravenous treatment regimens, were 0.792 (P ⫽ .001) and 0.799 (P ⬍ .001), respectively.9 Another series of preclinical experiments conducted at the Netherlands Cancer Institute by one of our PhD students demonstrated an advantage of using hyperthermia to increase the platinum drug exposure of peritoneal tumors.10-12 Increasing local drug concentration by intraperitoneal administration in combination with hyperthermia is therefore attempted as a way to overcome platinum drug resistance. Unfortunately, the application of hyperthermia in the clinical setting poses an additional logistic challenge over the already complex intraperitoneal drug administration. Nevertheless, the promising results with intraperitoneal platinum, combined with hyperthermia, have led to a multicenter phase III randomized clinical trial in the Netherlands for stage III ovarian carcinoma, randomly assigning patients to secondary debulking surgery with or without hyperthermic intraperitoneal chemotherapy—the OVHIPEC (Ovarian Cancer Hyperthermic Intraperitoneal Chemotherapy) study (ClinicalTrials.gov identifier NCT00426257). The trial, which is led by Dr van Driel of the Netherlands Cancer Institute in Amsterdam, is nearing completion of accrual. © 2015 by American Society of Clinical Oncology
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Activation of coagulation cascade Increased TAT complexes
Angiogenesis EC proliferation Hyperpermeability
Vascular homeostasis
lmmunomodulation
Kidney function
Fig 2. Multiple biologic effects of vascular endothelial growth factor (VEGF). Data adapted.13 EC, endothelial cell; TAT, thrombin-antithrombin.
Bone marrow function Blood pressure
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Vascular endothelial growth factor (VEGF) has multiple biologic activities (Fig 2).13 I will discuss two roles of VEGF in particular: that is, activation of the coagulation cascade resulting in enhanced formation of thrombin-antithrombin (TAT) complexes and many other coagulation factors (eg, tissue factor, Von Willebrand factor), stimulation of angiogenesis through endothelial cell proliferation and induction of hyperpermeability, and the interplay between platelets and VEGF in tumor angiogenesis.14-17 I made an intriguing observation in a patient with locally advanced breast cancer receiving doxorubicin plus cyclophosphamide. I noticed a striking synchronization of platelet count and serum VEGF, from which we concluded that platelets are carriers of VEGF and that chemotherapy affects the status of the platelet-VEGF system (Fig 3). In a phase I study, we found that the addition of semaxanib (SU5416), an inhibitor of VEGF receptor tyrosine kinase, to cisplatin-gemcitabine chemotherapy in patients with non–small-cell lung cancer increased intravascular coagulation, as evidenced by an increase in the level of TAT complexes and several other coagulation factors, compared with chemotherapy or semaxanib alone.18,19 These observations taught us that a thorough evaluation of coagulation is warranted each time a new VEGF inhibitor is evaluated in phase I. A 40-year-old patient with a soft tissue sarcoma who participated in our phase I study with semaxanib taught us a lesson about VEGF
0
0 0
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Time (weeks) Fig 3. Synchronization of platelet count and serum vascular endothelial growth factor (VEGF) in patient receiving chemotherapy. 512
© 2015 by American Society of Clinical Oncology
and endothelial leakage. Before the start of treatment and while receiving treatment, this patient had massive fluid accumulation in the center of a tumor in the left upper abdomen. We decided to draw fluid from this lesion and collected 600 mL of fluid, which seemed to have a 450-fold increased VEGF concentration compared with plasma and a 63-fold increased level of TAT complexes. Intratumoral fluid leaking from the surrounding tumor tissue can therefore be considered a “VEGF bomb,” which may exert pronounced effects on angiogenesis, coagulation, and bleeding tendency, all at the same time, in patients treated with drugs affecting the VEGF signaling pathway. Subsequently, we collected intratumoral fluid from 12 patients with soft tissue sarcomas.17 This process of intratumoral leakage is known to occur in other tumor types as well, but to a lesser extent, as a result of leakage of fluid from the tumor tissue. It is more pronounced in soft tissue sarcoma because of the nature of the tissue, which promotes fluid accumulation, and because of the fact that this tumor type forms a pseudo capsule, which retains the fluid within the tumor.
EPIGENETICS
Our work on epigenetics dates back to the 1970s. During one of my trips to the US National Cancer Institute, the drug decitabine, also know as 5-aza-2=-deoxcytidine, was offered to me as an experimental agent for further development in Europe within the European Organisation for Research and Treatment of Cancer. Decitabine induces DNA hypomethylation through inhibition of the enzyme DNA methyltransferase and thereby inhibits gene function. After we had conducted preclinical xenograft evaluations, which demonstrated schedule dependency20 and preclinical toxicology through the New Drug Development Office, the drug entered a phase I study in solid tumors at the VUMC in 198321 and additional studies in leukemia and myelodysplastic syndromes as of 1985. These studies fuelled interest in the drug in other parts of the world, which contributed to its current status as an approved treatment option (Dacogen; Otsuka Pharmaceutical, Tokyo, Japan) in acute myeloid leukemia and myelodysplastic syndromes. Of interest, a patient with a melanoma in the left nose fold (melanoma according to a recent retrospective diagnostic procedure using stored tumor tissue [originally diagnosed as an undifferentiated carcinoma]) participated in our phase I study of decitabine. The facial lesion had been treated with radiotherapy 1 year earlier. Not only did JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
his facial lesion show a dramatic response within 3 months of the start of treatment with decitabine, there was also considerable shrinkage of an involved lymph node in his neck. The node, while it was shrinking, was surgically excised and diagnosed (also retrospectively) as a melanoma metastasis with extensive infiltration of CD8⫹ T cells. Subsequently, the node area was irradiated, resulting in a durable remission for 1 year while on continued treatment with decitabine, followed by progression of the facial lesion. The lesson we learned from this pearl is that we always have to remain open to the possibility of exceptional unexpected responses. In retrospect, looking at the extensive T-cell infiltration in the metastatic lesion, we can say that we should have continued decitabine treatment, because this drug also has an immunologic component to its action profile. My work in the field of DNA methylation is still continuing, although in a different area: screening and early diagnosis of malignancies. In collaboration with colleagues at Technical University Twente in the Netherlands, I am developing a “smart pill” that detects hypermethylation of promoter regions of genes related to tumorigenesis in the GI tract. This nanopill concept is quite straightforward: one swallows a pill-like object that analyses the fluids it passes through during its journey down the GI tract for epigenetic tumor markers. The fluid entering the nanopill passes through a microfluidic affinity filter consisting of microscopic silicon pillars, functionalized with proteins that bind (hyper)methylated DNA. Methylated DNA is bound to the filter, resulting in a sample that contains all (hyper)methylated DNA. The resulting single-stranded DNA interacts with a detector. We use DNA probes complementary to the genes that are clinically proven to be related to cancer when their promoters are hypermethylated. These probes hybridize with the single-stranded DNA from the filter, thereby inducing a signal, which indicates that the gene that corresponds to that specific probe was hypermethylated. The detector then sends a signal to the person’s smart phone, and he or she may take action (eg, request a colonoscopy or positron emission tomography [PET] scan, also looking for tumors of organs draining onto the GI tract). The concept is currently under development using urine as the source of (hyper)methylated gene promoters to detect recurrence of bladder cancer.22-24 To create a working smart pill for the early detection of GI malignancies, miniaturization of the technology will be essential.
PERSONALIZED MEDICINE
The term personalized medicine refers to the incorporation of the patient’s tumor-specific characteristics into clinical decision making. Targeted drug treatment based on individual features of growth factor signaling pathways in the patient’s tumor, such as clinically relevant mutations of one or more elements of a pathway, is one of the ways personalized medicine is practiced. Important points of attack for targeted therapies, particularly for tyrosine kinase inhibitors, are intracellular tyrosine kinases associated with a growth factor receptor or regulatory proteins further downstream in the signaling pathway. Mutations of the genes of these regulatory proteins may lead to constitutive activation of the signaling cascade, causing uncontrolled cell division and tumor progression. The presence of such mutations may be determined by means of sequencing of the kinase genes. Absence or presence of mutated kinases provides important information on which treatment decisions can be based. www.jco.org
A 58-year-old female painter presented with right-sided locally advanced breast cancer and positive axillary nodes. The tumor was estrogen receptor (ER) positive and human epidermal growth factor receptor 2 negative. She received six cycles of neoadjuvant chemotherapy before breast-saving tumor excision. Subsequently, she received radiotherapy and long-term hormonal therapy with anastrozole. After 6 years of anastrozole treatment, she developed a single metastasis in the left lung, and lobectomy was performed. The metastasis was indeed ER positive. Postoperatively, hormonal treatment was switched to tamoxifen. One year later, she developed bone metastases. A plausible explanation for ER resistance to hormonal therapy in breast cancer may be post-translational modifications, such as ER phosphorylation. According to the literature, at least three kinase-regulated pathways may lead to ER phosphorylation and thus resistance: the RAF, mammalian target of rapamycin (mTOR), and protein kinase A (PKA) pathways.25-27 To determine how to overcome the resistance to hormonal therapy in our patient, tissue lysate of the resected lung metastasis was subjected to the PamGene (‘s-Hertogenbosch, the Netherlands) kinase platform, an alternative for tumor profiling by full genomic sequencing, focusing on drug target and (resistance) pathway activities. This study, conducted by Ruijtenbeek et al at PamGene, yielded evidence that mTOR inhibition (by dactolisib [BEZ235], an enzymatic inhibitor of mTOR, mimicking the effect of the mTOR blocker everolimus) and PKA inhibition (by a PKA inhibitor peptide) might overcome phosphorylation-dependent hormone resistance in this patient, whereas RAS-RAF-MEK-Erk pathway inhibition and Akt inhibition would not (Fig 4). Therefore, it was decided to continue the treatment of our patient with the combination of the aromatase inhibitor exemestane and the approved mTOR inhibitor everolimus. This treatment was started fairly recently, and initial signs are favorable (ie, lowering of serum tumor marker). This is in line with the positive data (improved progression-free survival) reported by Baselga et al28 for the combination of aromatase and mTOR inhibition using the same drug combination in postmenopausal patients with hormone receptor– positive advanced breast cancer. Should our patient experience progression on the current combination, we still have the option of treating the patient with a PKA inhibitor. Molecular imaging is becoming an important tool in the development and application of personalized medicine. The VU University and VUMC are leading institutes in the field of radiopharmaceuticals and sophisticated radioimaging. I will briefly review the work conducted by Van Dongen et al in the field of immuno-PET imaging using the zirconium-89 (89Zr) –labeled anti– c-Met antibody DN30. Quantitative PET imaging of Met-expressing human cancer xenografts was demonstrated in nude mice using DN30.29 This antibody may therefore be useful as an imaging tool in patients as an alternative for biopsies, if frequent biopsies are not feasible, and as a tool to detect different tumor clones. Furthermore, c-Met expression has been demonstrated to be an important determinant of resistance to epidermal growth factor receptor (EGFR) inhibitors.30 An example of the clinical use of radiopharmaceuticals and PET imaging is provided by the work of Bahce et al31 comparing patients with non–small-cell lung cancer with wild-type EGFR and those with an EGFR exon-19 deletion to predict drug resistance. This deletion confers responsiveness to EGFR tyrosine kinase inhibitors. PET imaging using [18F]fluorodeoxyglucose did not distinguish these patients, whereas PET imaging using [11C]erlotinib clearly did (Fig 5). This © 2015 by American Society of Clinical Oncology
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AKT
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Sorafenib ERα Fig 4. Which drug should be added to an aromatase inhibitor in a patient with breast cancer developing estrogen receptor (ER) resistance? Results of PamGene kinase platform (reprinted with permission from R. Ruijtenbeek). mTOR, mammalian target of rapamycin; PKA, protein kinase A.
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noninvasive procedure allows differentiation of drug-sensitive and drug-resistant patients before the treatment is actually given, thereby saving patients noneffective treatments.32 IMMUNOTHERAPY
The report by Rosenberg et al33 on autologous lymphokine-activated killer cells and interleukin-2 in patients with metastatic cancer published in 1985 triggered me to embark on translational immunotherapy research. Today, cancer immunotherapy continues to be an important research theme at the VUMC Cancer Center Amsterdam (CCA). Under the motto “use the primary to treat the patient,” we have successfully modulated the patient’s adaptive immune system, targeting it toward the patient’s own tumor cells to eradicate residual disease after local treatment.34-36 One of the first patients we treated with an autologous vaccine (AV) in this way was a 58-year-old Brazilian man with
Wild-type EGFR
EGFR exon 19 deletion
[18F]FDG
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Fig 5. Prediction of resistance to epidermal growth factor receptor (EGFR) inhibitors in non–small-cell lung cancer using positron emission tomography imaging (reprinted and adapted with permission31). FDG, fluorodeoxyglucose. 514
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S100-positive melanoma. After resection of eight lung metastases, we prepared an AV of his metastases. There were many aggregates of lymphoid cells in between the tumor tissue and dense infiltration by activated CD8⫹ T cells, resembling reactive lymph follicles (Fig 6). The vaccine was administered intradermally every 3 weeks for four cycles and then every 3 months for a total of 2 years. At 2 years, a new lung lesion appeared, which was resected, and AV was resumed and continued for another 2 years. The microscopic observation of intrametastatic follicles of CD3⫹, CD4⫹, and CD8⫹ lymphocytes in the patient’s postvaccination metastasis indicated the promise of immunologic efficacy of our AV procedure. After a treatment-free period, the patient developed progressive chemotherapy-resistant lymphoma. At age 63 years, he died. Stimulated by the findings in this patient, we conducted a phase II study of AV with Bacillus Calmette-Guérin as vaccine adjuvant in 81 patients with American Joint CC stage III to IV melanoma and at least one resectable metastasis.35 Whenever feasible, radical metastasectomy was performed. Intradermal AV was started 4 to 5 weeks postoperatively and continued at a frequency of once every 3 weeks. Five-year survival was 48% and 34% in patients with stage III and IV disease, respectively. The degree of delayed-type hypersensitivity correlated with survival. No evidence of disease after surgery and the presence of tumor-associated antigen–specific cells in the tumor were prognostic. Another important AV study we conducted was a randomized phase III study in patients with CRC, stage II or III, one of the earliest of its kind.36 AV plus Bacillus Calmette-Guérin was administered intradermally. According to a recent evaluation, 15-year recurrencefree survival in the vaccinated group was significantly greater than in the control group.37 The effect of long-term administration of granulocytemacrophage colony-stimulating factor (GM-CSF), in combination with conventional neoadjuvant chemotherapy, on dendritic cell JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
A
B
Fig 6. Intrametastatic lymphoid follicles in patient with melanoma. HE, hematoxylin and eosin.
CD3+
HE
C
D
CD4+
CD8+
activation and clinical end points was studied in patients with locally advanced breast cancer.38-40 GM-CSF was chosen for its immunostimulatory effects (eg, in vivo recruitment and activation of dendritic cells) to achieve in vivo vaccination on chemotherapy-induced tumor antigen release. The trial showed a high response rate and good 3-year disease-free and overall survival rates, which compared favorably with results of previous studies in locally advanced breast cancer.38 It was hypothesized that these encouraging results were related to the prolonged presence of the primary tumor and to the long-term administration of the immunostimulant in the presence of the primary tumor and the axillary lymph nodes. A more recent vaccination phase I study in metastatic castrateresistant prostate cancer examined the feasibility of using a vaccine
derived from two prostate tumor cell lines, transduced to express and release GM-CSF (allogeneic GVAX; Cell Genesys, South San Francisco, CA), in combination with the anti–CTLA-4 monoclonal antibody ipilimumab at dosages ranging from 0.3 to 5.0 mg/kg every 4 weeks.41 This study represented the first clinical study of combined tumor vaccination and immune checkpoint inhibition. Remarkable remissions based on prostate-specific antigen responses (confirmed in some cases by bone scans) were observed, particularly in the expansion cohort treated at the 3.0-mg/kg ipilimumab dose. One patient at this dose level had a complete prostate-specific antigen response. Hypophysitis was a frequent adverse effect at the higher ipilimumab dose levels (3.0 and 5.0 mg/kg), but it was highly treatable with hormone replacement therapy, after which the scheduled study treatment could
Table 1. Guidance of Tumor Vaccination by T-Cell Profiling in Blood, Tumor, and Lymph Nodes Study
Tumor Type
Disease Stage
Baars et al,35 Haanen et al43 Melanoma
Metastatic
de Weger et al,37 Turksma et al (submitted for publication) Pinedo et al,40 Van Cruijsen et al (manuscript in preparation) Santegoets et al44
Primary, stage II to III
Colorectal cancer
Treatment Excision metastases plus autologous tumor cell vaccination Surgery plus autologous tumor cell vaccination
Locally advanced Primary, stage III to IV Neoadjuvant breast cancer chemotherapy plus in vivo vaccination Prostate cancer Advanced, hormone Allogeneic GVAX resistant vaccination
Immunostimulant
Predictive Factors
BCG
Melanoma-specific TILs, but not circulating CD8⫹ T cells
BCG
MSI/MSS, CD8 T-cell infiltration
GM-CSF
Lymph node DC rates and activation pretreatment Treg cells
Ipilimumab
Teff-to-Treg ratio and CTLA-4–positive Th cells, high DCs, low MDSC frequency
Abbreviations: BCG, Bacillus Calmette-Guérin; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; MDSC, myeloid-derived suppressor cell; MSI, microsatellite instability; MSS, microsatellite stability; Teff, effector T cell; Th, T helper cell; TIL, tumor-infiltrating lymphocyte; Treg, regulatory T cell.
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be resumed. Hypophysitis is a commonly reported autoimmune effect of anti–CTLA-4 antibodies that is mediated by pituitary expression of CTLA-4.42 Our vaccination studies in four different tumor types, using AV or allogeneic GVAX and increasingly powerful immunostimulants, have demonstrated that T-cell profiling in blood, tumor, and lymph nodes can provide treatment guidance as predictive biomarkers (Table 1).35,37,40,43,44 I propose combining AV also with emerging powerful immunostimulants, such as the immune checkpoint modulators, targeting PD1 and PD-L1 and other new immune targets. Studies on T-cell profiling after anti-PD1 and other types of immunologic treatment are ongoing. VUMC CCA
Throughout my career at the VUMC, I have stressed the importance of translational cancer research to better understand what is happening in our patients and how their outcomes may be improved by conventional or, if indicated, unconventional treatment approaches. To facilitate translational research and promote cross pollination between the various disciplines involved, we created the VUMC CCA as an organizational entity focusing on translational research in the spirit REFERENCES 1. Pinedo HM, Giaccone G: P-glycoprotein: A marker of cancer-cell behavior. N Engl J Med 333: 1417-1419, 1995 2. Schuurhuis GJ, Broxterman HJ, van der Hoeven JJ, et al: Potentiation of doxorubicin cytotoxicity by the calcium antagonist bepridil in anthracycline-resistant and -sensitive cell lines: A comparison with verapamil. Cancer Chemother Pharmacol 20:285-290, 1987 3. Linn SC, Giaccone G, Pinedo HM: Complete remission of metastatic colorectal cancer: A pitfall in a multidrug resistance reversal trial. Lancet 343: 1648-1649, 1994 4. Linn SC, van Kalken CK, van Tellingen O, et al: Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. J Clin Oncol 12:812-819, 1994 5. Lankelma J, Dekker H, Luque FR, et al: Doxorubicin gradients in human breast cancer. Clin Cancer Res 5:1703-1707, 1999 6. Oldenburg J, Begg AC, van Vugt MJ, et al: Characterization of resistance mechanisms to cisdiamminedichloroplatinum(II) in three sublines of the CC531 colon adenocarcinoma cell line in vitro. Cancer Res 54:487-493, 1994 7. Alberts DS, Delforge A: Maximizing the delivery of intraperitoneal therapy while minimizing drug toxicity and maintaining quality of life. Semin Oncol 33:S8-S17, 2006 (suppl 12) 8. Hess LM, Alberts DS: The role of intraperitoneal therapy in advanced ovarian cancer. Oncology (Williston Park) 21:227-322, 2007 9. Hess LM, Benham-Hutchins M, Herzog TJ, et al: A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer. Int J Gynecol Cancer 17:561-570, 2007 10. Los G, Smals OA, van Vugt MJ, et al: A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity. Cancer Res 52:1252-1258, 1992 516
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of David Karnofsky. In 2006, all 15 research groups, which were scattered around the VU campus until that time, moved to the newly created CCA building, which is directly connected to the clinic building of the VUMC. Tissue samples, blood samples, and other bodily fluids taken in the clinic can be transferred to the laboratory immediately, and the results of the laboratory investigations go back to the clinic immediately. Clinicians are required to have worked in the laboratory for 1 to 2 years and to work in the laboratory for at least 1 day per week thereafter. Conversely, postdoctoral and PhD students are required to come to the clinic to actually see the clinicians at work there with the patients and nurses. In this way, the translational bridge will continue to be crossed in both directions, pushing the cancer field forward. To finish in the spirit of Baruch Spinoza, this will take us from pre-existent ideas to a deeper understanding that will ultimately benefit our patients. This is my most fervent wish.
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the author are available with this article at www.jco.org.
11. Los G, van Vugt MJ, den Engelse L, et al: Effects of temperature on the interaction of cisplatin and carboplatin with cellular DNA. Biochem Pharmacol 46:1229-1237, 1993 12. Los G, van Vugt MJ, Pinedo H: Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer 69:235-241, 1994 13. Verheul HM, Pinedo HM: Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7:475-485, 2007 14. Verheul HM, Hoekman K, Luykx-de Bakker S, et al: Platelet: Transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187-2190, 1997 15. Pinedo HM, Verheul HM, D’Amato RJ, et al: Involvement of platelets in tumor angiogenesis? Lancet 352:1775-1777, 1998 16. Verheul HM, Jorna AS, Hoekman K, et al: Vascular endothelial factor stimulated endothelial cells promote adhesion and activation of platelets. Blood 96:4216-4221, 2000 17. Verheul HM, Hoekman K, Lupu F, et al: Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin Cancer Res 6:166-171, 2000 18. Kuenen BC, Rosen L, Smit EF, et al: Dose finding and pharmacokinetic study of cisplatin, gemcitabine and SU5416 in patients with solid tumors. J Clin Oncol 20:1657-1667, 2002 19. Marx GM, Steer CB, Harper P, et al: Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: Time to take stock! J Clin Oncol 20:1446-1448, 2002 20. Braakhuis BJ, van Dongen GA, van Walsum M, et al: Preclinical antitumor activity of 5-aza-2=deoxycytidine against human and neck cancer xenografts. Invest New Drugs 6:299-304, 1988 21. Van Groeningen CJ, Leyva A, O’Brien AM, et al: Phase I and pharmacokinetic study of 5-aza-2=deoxycytidine (NSC 127716) in cancer patients. Cancer Res 46:4831-4836, 1986 22. Enokida H, Nakagawa M: Epigenetics in bladder cancer. Int J Clin Oncol 13:298-307, 2008
23. Hoffman AM, Cairns P: Epigenetics of kidney cancer and bladder cancer. Epigenomics 3:19-34, 2011 24. Sánchez-Carbayo M: Hypermethylation in bladder cancer: Biological pathways and translational applications. Tumour Biol 33:347-361, 2012 25. De Leeuw R, Neefjes J, Michalides R: A role for estrogen receptor phosphorylation in the resistance to tamoxifen. Int J Breast Cancer 2011: 232435, 2011 26. Thomas RS, Sarwar N, Phoenix F, et al: Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-␣ activity. J Mol Endocrinol 40:173-184, 2008 27. Tokunaga E, Hisamatsu Y, Tanaka K, et al: Molecular mechanisms regulating the hormone sensitivity of breast cancer. Cancer Sci [epub ahead of print on August 26, 2014] 28. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptorpositive advanced breast cancer. N Engl J Med 366:520-529, 2012 29. Perk LR, Stigter-van Walsum M, Visser GW, et al: Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30. Eur J Nucl Med Mol Imaging 35:1857-1867, 2008 30. Boccaccio C, Luraghi P, Comoglio PM: METmediated resistance to EGFR inhibitors: An old liaison rooted in colorectal cancer stem cells. Cancer Res 74:3647-3651, 2014 31. Bahce I, Smit EF, Lubberink M, et al: Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res 19:183-193, 2013 32. Poot AJ, Slobbe P, Hendrikse NH, et al: Imaging of TKI-target interactions for personalized cancer therapy. Clin Pharmacol Ther 93:239-241, 2013 33. Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485-1492, 1985 JOURNAL OF CLINICAL ONCOLOGY
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
34. Baars A, Buter J, Pinedo HM: Making use of the primary tumour. Bioessays 25:79-86, 2003 35. Baars A, Claessen AM, van den Eertwegh AJ, et al: Skin tests predict survival after autologous tumor cell vaccination in metastatic melanoma: Experience in 81 patients. Ann Oncol 11:965-970, 2000 36. Vermorken JB, Claessen AM, van Tinteren H, et al: Active specific immunotherapy for stage II and stage III human colon cancer: A randomised trial. Lancet 353:345-350, 1999 37. de Weger VA, Turksma AW, Voorham QJ, et al: Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin Cancer Res 18:882-889, 2012 38. Honkoop AH, Luykx-de Bakker SA, Hoekman K, et al: Prolonged neoadjuvant chemotherapy with
GM-CSF in locally advanced breast cancer. Oncologist 4:106-111, 1999 39. Luykx-de Bakker SA, Verheul HM, de Gruijl TD, et al: Prolonged neoadjuvant treatment in locally advanced tumours: A novel concept based on biological considerations. Ann Oncol 10:155160, 1999 40. Pinedo HM, Buter J, Luykx-de Bakker SA, et al: Extended neoadjuvant chemotherapy in locally advanced breast cancer combined with GM-CSF: Effect on tumour-draining lymph node dendritic cells. Eur J Cancer 39:1061-1067, 2003 41. Van den Eertwegh AJ, Versluis J, van den Berg HP, et al: Combined immunotherapy with granulocyte-macrophage colony-stimulating factortransduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-
resistant prostate cancer: A phase 1 dose-escalation trial. Lancet Oncol 13:509-517, 2012 42. Iwama S, De Remigis A, Callahan MK, et al: Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 6:230ra45, 2014 43. Haanen JB, Baars A, Gomez R, et al: Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 55: 451-458, 2006 44. Santegoets SJ, Stam AG, Lougheed SM, et al: T cell profiling reveals high CD4⫹CTLA-4⫹ T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother 62:245-256, 2013
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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The 42nd David A. Karnofsky Memorial Award Lecture: Understanding The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Herbert M. Pinedo Stock or Other Ownership: Jennerex, Gilde Healthcare Services, VitrOmics Healthcare Services, PamGene Consulting or Advisory Role: Spectrum Pharmaceuticals, VitrOmics Healthcare Services, PamGene, Gilde Healthcare Services, Bristol-Myers Squibb, sanofi-aventis Travel, Accommodations, Expenses: Bristol-Myers Squibb, Spectrum Pharmaceuticals
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Understanding: 42nd David A. Karnofsky Memorial Award Lecture
Acknowledgment I thank the many clinicians and scientists who contributed to the work described in this article, in particular the members of my staff over the years at the VU University Medical Center: Victor van Beusechem, Epie Boven, Henk Broxterman, Jan Buter, Fons van den Eertwegh, Winald Gerritsen, Giuseppe Giaccone, Cees van Groeningen, Tanja de Gruijl, Hidde Haisma, Klaas Hoekman, Bart Kuenen, Frank Kruyt, Jan Lankelma, Frits Peters, Rik Scheper, Gerrit Jan Schuurhuis, Jan Vermorken, Wim van der Vijgh, and Elsken van der Wall. I also thank Joke van Diemen and Marinus Lobbezoo for editorial and writing assistance.
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