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ScienceDirect The role of active vaccination in cancer immunotherapy: lessons from clinical trials Haydn T Kissick1,2 and Martin G Sanda1 In the past few years, a number of different immunotherapeutic strategies have shown impressive results in cancer patients. These successful approaches include blockade of immunosuppressive molecules like PD-1 and CTLA-4, adoptive transfer of patient derived and genetically modified Tcells, and vaccines that stimulate tumor antigen specific Tcells. However, several large vaccine trials recently failed to reach designated primary endpoints. In light of the success of other immunotherapeutic approaches, these negative results raise the questions of why vaccines have not generated a better response, and what the role of active vaccination will be moving forward in cancer immunotherapy. Addresses 1 Department of Urology, Emory University School of Medicine, United States 2 Department of Microbiology and Immunology, Emory University School of Medicine, United States Corresponding author: Kissick, Haydn T ([email protected])

Current Opinion in Immunology 2015, 35:15–22 This review comes from a themed issue on Vaccines Edited by Rafi Ahmed and John R Mascola

http://dx.doi.org/10.1016/j.coi.2015.05.004 0952-7915/# 2015 Published by Elsevier Ltd.

Introduction Several impressive results have recently been achieved using immunotherapy to treat a range of different cancers. In 2010, the first results from two phase-III trials investigating Ipilimumab (anti-CTLA-4) found that this drug significantly improved survival of patients with melanoma [1,2]. More recently, clinical trials investigating antibodies blocking PD-1 to treat melanoma have achieved objective response rates of between 28% and 52% in large phase I and III studies, and based on these data, anti-PD1 is now approved to treat this cancer [3–6]. Following the success in melanoma, PD1 blockade has also shown clinical anti-cancer efficacy in lung cancer, lymphoma, bladder cancer, kidney cancer and ovarian cancer [3,7,8]. In addition to these treatments that block immunosuppressive mechanisms, there are numerous treatments that aim to boost the www.sciencedirect.com

existing immune response to the tumor. The most successful of these therapies, adoptive cell transfer, isolates CD8 T-cells from the tumor of a patient, expands the cell population over 1000-fold with IL-2 treatment, and then re-infuses the cells back into the patient. This approach has generated some of the most impressive results in several clinical trials for melanoma, with objective response rates consistently around 50%, and complete responses in up to 22% of patients [9]. To build on the success of adoptive cell transfer, the use of CD8 T-cells that have been genetically modified to express a T-cell receptor able to directly recognize surface antigens on the tumor are under investigation in several cancers [10]. Initial studies of this treatment approach were successful in small groups of patients with both acute and chronic lymphoid leukemia [11,12]. Recently, data from the first phase I/IIa trial with 30 leukemia patients showed that 67% of patients underwent sustained remission, including some patients who had already failed stem-cell transplantation [13]. Together, these recent results demonstrate that therapeutic manipulation of the immune system is a new treatment strategy for many cancers. Although immunotherapy is set to be a new modality to treat cancer, the role of vaccines in this treatment approach is still unclear. Currently, the only vaccine FDAapproved for use is Provenge, an autologous dendritic cell vaccine targeting the prostate cancer antigen Prostatic Acid Phosphatase (PAP). Despite this initial success, and countless phase II trials showing some degree of vaccine efficacy in many other cancers, no other cancer vaccine has been approved for treatment thus far. Furthermore, at least five phase III vaccine trials have failed to reach the designated end points in the last two years. These failures raise the question that if T-cell adoptive transfer or treatments targeting CTLA-4 or PD1 can generate such astounding results, why are vaccines unable to do the same?

Using vaccines to treat cancer The feasibility of using a tumor antigen-targeted vaccine to treat cancer was proven when T-cells were identified that recognized the melanoma expressed gene, Mage A1 (MZ2-E) [14]. Since this discovery, many tumor antigens have been discovered that could be targeted by vaccines [15–17]. Based on these discoveries, several approaches using traditional antigen delivered in various adjuvants have been used to expand a population of tumor antigen specific T-cells. The most successful of these vaccines, Current Opinion in Immunology 2015, 35:15–22

16 Vaccines

Provenge, was approved to treat metastatic castration resistant prostate cancer after three separate phase III trials showed improved patient survival [18,19,20]. The first two trials had primary end points of time to disease progression that were not met. However, in both these trials, patients had an increased overall survival. Therefore, a third trial was designed with 512 patients and the primary end point was set as overall survival [19]. This trial generated the same results of the first two trials, a 4month increase in overall patient survival, and based on these data, Provenge became the first vaccine approved for the treatment of any cancer. Following this success, a peptide derived from the melanoma antigen, gp100 (PMEL), generated a modest improvement in time to progression free survival of 0.6 months ( p = 0.008) albeit without significant improvement in overall survival, further indicating that active vaccination is a feasible approach to induce an immune response to cancer [21]. Based on these results and several phase II trials, there are now phase III clinical trials investigating therapeutic vaccines for almost every cancer [22]. However, in the past 18 months, several phase III vaccine trials have failed to reach the primary endpoints of overall survival or progression free survival. Nevertheless, there are a number of key observations that indicate that vaccines can be successful in subsets of patients or in the correct treatment combinations.

The lesson from clinical trials Several trials have found that patients have a highly variable response to cancer vaccines. Recent data from phase II and III trials investigating a vaccine targeting MAGE-A3 for non-small cell lung cancer have demonstrated this problem. This vaccine uses the full length MAGE-A3 protein administered in the AS15 or AS02B adjuvant to induce an anti-tumor T-cell response. The phase II trial targeting MAGE-A3 in non small cell lung cancer showed a very weak trend towards improved patient survival, but failed to meet any of the primary or secondary end points [23]. However, based on the safety of the drug, and suggestion in the data that there was a subset of patients that responded to treatment, the phase III MAGRIT trial was initiated. In this trial 2278 patients who had undergone tumor resection and had confirmed MAGE A3 positive tumors were recruited. This trial was terminated due to lack of efficacy in extending disease-free survival or overall survival, but analysis of patients receiving the MAGE-A3 vaccine in both this trial and melanoma identified a gene signature of the tumors before immunization that predicted high responsiveness to the vaccine [24]. Interestingly, much of this gene signature belonged to genes that implied the presence of active immune cells in the tumor, including CD3, GZMK, CD86, CD11a, various MHC-II alleles (HLA-DR, DM and DQ) and several chemokines. In the 61/157 patients receiving the vaccine with this gene signature, the disease free interval hazard ratio was Current Opinion in Immunology 2015, 35:15–22

0.42. In comparison, gene signature negative patients had a disease free interval hazard ratio of 1.17 [25]. Similar findings were reported in the phase II IMA901 vaccine trial for renal cell carcinoma, where better disease control correlated best with the number of epitopes a patient responded to [26]. Additionally, phase II studies investigating Provenge found an association between the immune response to the target antigen and disease free survival [27], and one of the phase III trial found a correlation between PAP antibody titer and patient survival [19]. Together, these data indicate that the success of anti-cancer vaccines is dependent on how well the immune system of a patient can respond (Table 1). More importantly, this data suggests that there are a large proportion of patients whose response to vaccines is compromised. Whether this is due to a suboptimal target antigen, or represents a broader immune deficiency has not been consistently measured nor reported. However, this problem of non-responsiveness to therapeutic vaccines may be best illustrated by vaccine and immunotherapy trials in melanoma. Since 2000, multiple phase III vaccine trials for melanoma have failed to reach their primary clinical endpoint. Most recently the DERMA trial of 1351 patients receiving a MAGE-A3 vaccine failed to extend disease free survival [28]. This follows failures of Canavaxin, Melacine, various peptide and dendritic cell vaccines, an HSP96 targeting vaccine, and melanoma cell lysate vaccines [29]. The only successful vaccine trial for melanoma was the gp100 peptide with IL-2 that showed a 0.6 month increase in progression free survival ( p = 0.008) and a non-significant increase in overall survival from 11.1 months to 17.8 months ( p = 0.06) [21]. However this same vaccine failed to reach primary endpoints in earlier phase II trials [30]. By contrast, four separate clinical trials investigating PD1 blockade in melanoma have shown complete response rates around 20%, and objective responses in almost 50% of patients [3–6]. Ipilimumab, an antibody blocking CTLA-4, increased overall survival of melanoma patients by 3.7 months [1]. The combination of Nivolumab, an antibody blocking PD-1, and Ipilimumab generated at least 80% reduction in tumor volume in greater than 50% of patients [31]. Also, as discussed earlier, adoptive CD8 T-cell transfers for melanoma consistently achieve an objective response in approximately 50% of patients [9]. Together, these trials show that immunotherapies targeting PD-1 or CTLA4 are effective for melanoma, but vaccines specifically are not effective in this setting. The key difference between these treatment approaches is the mechanism of action. PD1 and anti-CTLA4 treatments restore the functionality of exhausted anti-tumor CD8 T-cells, which are plentiful in the tumors and periphery of healthy people and melanoma patients [32,33]. Adoptive transfer protocols simply bypass the natural mechanisms needed to expand the CD8 T-cells by performing this step ex vivo. In www.sciencedirect.com

Therapeutic vaccines to treat cancer Kissick and Sanda 17

Table 1 Overview of results from phase III vaccine trials and immune correlates to better patient outcomes Trial/name

Cancer

Antigen

Adjuvant/delivery

Patients

Primary endpoint

Immune correlates to improved outcome

DERMA

Melanoma

MAGE-A3

AS15, AS02B

1351

Disease free survival — data pending

MAGRIT

Lung

MAGE-A3

AS15, AS02B

2278

Disease free survival, Terminated due to futility

Tecemotide/ SMART Trial

Lung

MUC1

Liposome

1239

Overall survival, 25.6 versus 22, p = 0.12

IMA-901

Kidney

Multiple HLA-A2.1 peptides (10)

GM-CSF

Provenge/ IMPACT Study

Prostate

Autologous dendritic cells

512

gp100

Melanoma

Prostatic Acid Phosphatase PAP gp100

Montanide/IL-2

185

STn-KLH

Breast

Sialyl-Tn-KLH

KLH/Detox B

68

1022

comparison, vaccines require an intact immune system that can effectively present the vaccine antigen, and a population of tumor antigen specific T-cells capable of responding to this antigen. In most cancers, including melanoma, it is well reported that dendritic cell population is deficient in many ways [34–37], and T-cells are exhausted after long-term exposure to the tumor antigens [38,39]. In this immunological setting it is not entirely unexpected that vaccination produces sub-optimal outcomes (see Figure 1).

Cancer vaccines in a dysfunctional immune system The magnitude of the immune dysfunction in cancer can be quantified by comparing the outcome of vaccines in healthy patients to what is achieved by current cancer vaccines. Two of most effective human viral vaccines, YF-vax for yellow fever and Dryvax for small pox induce a CD8 T-cell population of around 5-30% of the entire CD8 population in the peripheral blood [40,41]. As there are approximately 4  1010 total CD8 T-cells in the human body, this translates to approximately 2– 12  109 cells induced by these vaccines [42]. In comparison to these viral vaccine regimes in healthy host, current www.sciencedirect.com

Phase II, saftey and tolerability were met. Phase III trial is currently underway Survival hazard ratio, 0.59, p = 0.01 Median overall survival 25.8 versus 21.7 Progression free survival, 2.2 versus 1.6, p = 0.008 Time to progression, 3.4 versus 3.0, p = 0.305 Overall survival, 23.1 vs. 22.3

References

Gene signature (GS) suggesting active immune response within the tumor from Phase II data GS+ patients versus placebo, HR = 0.37, p = 0.06 Gene signature suggesting active immune response within the tumor GS+ patients versus placebo, HR = 0.42, p = 0.06 Concurrent Radiation + vaccine. Overall survival 30.8 versus 20.6, p = 0.016 Multiple eptiope response correlated with better disease controll, p = 0.023

[25,28]

Antibody titre >400, Increased overall survival p = 0.001, 28.5% of patients

[18–20]

No correlation with immune activity in Phase II or III trial

[21,30]

Median or greater IgG response. Overall survival 39.6 versus 25.4, p = 0.005

[67,68]

[23,24,25]

[48]

[26]

cancer vaccines only induce around a 2-fold to 10-fold increase in antigen specific T-cells. Prostvac, a poxvirus modified to express Prostate Specific Antigen (PSA), increased the number of PSA specific T-cells in patients by on average 5-fold to produce 30 vaccine specific cells per million PBMCs [43,44]. This number is around 0.03% of the total CD8 T-cell population. The IMA901 trial for renal cancer defined a 4-fold increase in antigen specific cells over baseline as a positive response, with the precursor frequency of cells before vaccination usually being below the approximate 0.01% detection threshold [26]. Provenge generates a 5-fold increase to 20 cells per million PBMCs [45]. Also, the maximal response to the gp100 peptide vaccine for melanoma was only around a 2fold increase in antigen specific T-cells, and this was only achieved by a small percentage of patients [30]. There are a number of caveats to these numbers, such as other epitopes induced by some of the vaccines, or epitope spreading resulting in priming of non-vaccine antigens. Recently it was reported that treatment with Provenge resulted in a 5-fold increase of CD8 T-cells in the tumor, but this had no correlation with the response detected in the peripheral blood [45]. Although these are all possibilities, none fully explain the 100 fold less T-cells induced Current Opinion in Immunology 2015, 35:15–22

18 Vaccines

Figure 1

(a) Vaccine antigen specific T-cell pool

(b) APCs are not optimally immunogenic • Low co-stimulatory molecules • Low MHC-I • Poor cytokine production

is mostly exhausted

• Low proliferation in response to antigen • No cytokine production • High expression of PD1, LAG3, CTLA4

in the tumor microenvironment

• Up-regulation of PD-L1 by tumor cells • Secretion of immuno-suppressive molecules, e.g. TGF-β

Treatments:

Improve antigen

Rescue

• Antibody treatments blocking PD1 • siRNA against tumor produced TGF-β

presentation

T-cells CTLA4

PD1

LAG3

Treatments: • Antibody treatments blocking PD1, LAG3 and CTLA4 can restore the function of exhausted CD8 cells

(c) T-cells activated by vaccines are inhibited

Treatments: • Vaccines using ex-vivo optimally activated dendritic cells to deliver antigen (Provenge) • Co-treatment with radiation can improve antigen presentation • Powerful adjuvants can improve vaccine antigen presentation (e.g. CpG)

Inhibit local immune suppression TGF

Tumor Cell Current Opinion in Immunology

Immune dysfunction inhibiting vaccine efficacy in cancer, and treatments to overcome these problems: The immune system in cancer is damaged in several ways that limit the effectiveness of vaccines. However, new treatments targeting these mechanisms may offer opportunities to best the efficiency of current vaccines. (a) Vaccine antigen specific T-cells in cancer patients express high level of exhaustion markers that limit the effector functions of the cells. A key feature of exhausted CD8 T-cell is the inability to proliferate in response to antigen. If T-cell precursor proliferation is inhibited, vaccine efficacy is inhibited. Several pre-clinical and clinical trials have found that T-cell proliferation is increased after vaccination when these molecules are blocked using antibodies. (b) Antigen presenting cells in cancer express reduced amount of MHC-I and low levels of many co-stimulatory molecules. Without optimal antigen presentation, the T-cell response to the vaccine is limited. Vaccines like Provenge overcome this problem using ex vivo stimulated dendritic cell. Several different adjuvants or vaccine platforms are being tested with cancer vaccines to determine the best way to activate antigen-presenting cells. These include delivery of vaccine antigens in viral vectors, bacterial vectors or with TLR agonists. In addition to adjuvants, other therapies such as radiation also help activate antigen-presenting cells and there are opportunities to combine vaccines with current treatment approaches to generate a better response to the vaccine. (c) If vaccines can induce a T-cell response, numerous mechanisms limit the effectiveness of the T-cells that make it to the tumor. Expression of PD-L1 or production of immunosuppressive cytokines like TGF-b by tumor cells inhibits the cytotoxicity of T-cells that do make it to the tumor. New treatments that prevent tumors from producing immunosupressive cytokine by delivery of siRNA to the tumor are being investigated. Together these strategies offer several opportunities to boost vaccine efficacy.

by these vaccines compared to what the YF-vax or Dryvax vaccination induce. Although this comparison is somewhat disheartening, the fact that these small increases in vaccine specific cells can have an impact on patient survival is encouraging. Furthermore, if we could induce responses approaching that achieved by viral vaccines, it is logical to assume that a far better anti-cancer response could be generated. Therefore, the current challenge for cancer vaccines is determining if combining vaccines with other treatment modalities can overcome the dysfunctional immune system of cancer patients. Evidence that boosting the immune system before vaccination can generate a better response was suggested in recent small phase I trials combining vaccines with other immunotherapy, several of which are ongoing. One trial of a small group of patients receiving Ipilimumab and Prostvac found this combination boosted the frequency of antigen specific T-cells in comparison to single treatments [46]. Another phase I trial in prostate cancer found that treatment with GVAX-PCa, a vaccine containing 2 irradiated prostate cancer cell lines that express GM-CSF, in Current Opinion in Immunology 2015, 35:15–22

combination with Ipilimumab resulted in increased CD40 expression by dendritic cells, suggesting this combination may improve dendritic cell function in cancer patients [47]. In addition, a phase III trial of Tecemotide, a vaccine targeting MUCI to treat non-small cell lung cancer, showed efficacy in the predefined subgroup of patients that received concurrent chemoradiotherapy, but not in those receiving the vaccine alone (30.8 vs. 20.6 months, p = 0.016) [48]. Radiation has many effects that stimulate the anti-tumor immune response, including activating local dendritic cells, release of HMGB1 or increased release of tumor antigens which could all boost the efficacy of the vaccine [49]. Although encouraging, there are also combinations that failed to generate a better vaccine. For example, in a phase III trial with 676 patients, the gp100 peptide vaccine when given with Ipilimumab was no better than Ipilimumab alone [1]. A significant challenge is therefore deciding what treatment approach would complement vaccines best. Recently it has become clear that reversing exhaustion of CD8 cells by blocking PD1 can have powerful clinical effects in several cancers. www.sciencedirect.com

Therapeutic vaccines to treat cancer Kissick and Sanda 19

CD8 T-cell exhaustion and vaccines Given that a key feature of T-cell exhaustion is the lack of proliferation in response to antigen, and because vaccination is contingent on a population of CD8 T-cells able to divide, this mechanism obviously limits vaccine efficacy. This possibility means that understanding how exhaustion works in cancer, and how treatments targeting exhaustion interact with vaccine regimes is necessary for the success of vaccines. T-cell exhaustion was initially discovered when T-cells continually exposed to viral antigens resulted in progressive loss of function of these Tcells, instead of deletion as was previously thought [50,51]. This observation suggested that it might be possible to restore the function of the exhausted CD8 T-cells. Investigation of the mechanisms controlling the functional decline of CD8 cells persistently exposed to antigen found that PD1 contributes to this process, and that blockade of PD1 could rescue the exhausted cells [52]. Since this discovery, countless studies have found that exhaustion occurs in almost any setting where persistent antigen exposure occurs, and that PD1 blockade can partially restore the function of exhausted CD8 Tcells. Exhausted T-cells are found in most cancers, including breast, prostate, colon, and melanoma [53–57]. A key feature of exhaustion is the inability of T-cells to proliferate in response to antigen, and therefore the fact that PD1 is so successful in melanoma makes it unlikely that vaccination could ever be successful alone; the Tcells are functionally exhausted and non-responsive to vaccine antigen. For the future success of vaccines, it is therefore important to understand the mechanisms that control exhaustion. Since the discovery of PD1, several other surface receptors that have an important role in regulating CD8 exhaustion have been discovered, the best investigated being TIM3 and LAG-3. Several studies have found that LAG-3 contributes to exhaustion in mouse models of cancer, and is expressed by exhausted CD8 T-cells in many cancers [58–61]. Blockade of LAG-3 rescues exhausted CD8 T-cells in several cancer models, and various clinical trials investigating antibodies blocking this molecule are underway. A phase I trial of LAG-3 in combination with vaccination has been reported. In this trial, an antibody, IMP321, was given to patients to block LAG-3 in combination with a melanoma vaccine targeting MART-1. Five out of six patients had an increase in the MART-1 specific T-cells when given the vaccine in combination with LAG-3 inhibition, while only one of six patients had an increased T-cell response to the vaccine alone [62]. TIM3 is another molecule that contributes to CD8 T-cells exhaustion discovered in HIV patients, and blockade of TIM3 was found to restore the functionality of exhausted CD8 T-cells isolated from HCV patients [63,64]. Several observations have now been made in human patients with cancer and mouse models of cancer that show that tumor antigen specific www.sciencedirect.com

CD8 T-cells express high levels of TIM3 [39,54,55,65]. No clinical trials of TIM3 blockade have been reported yet, but in vitro experiments have found that blockade of PD1 and TIM3 improved the response of CD8 T-cells from patients with melanoma against the NY-ESO-1 antigen, further suggesting that rescuing exhausted CD8 cells before immunization could generate a better immune response to the vaccine [66]. Together, these studies indicate that PD1 blockade is just the first of many treatments that can rescue exhausted CD8 T-cells, and there are numerous treatment options being developed that will be able to target this dysfunction. Furthermore, how these treatments interact with vaccine strategies in cancer is still an ongoing question.

Conclusion Vaccines to treat cancer have had far more failures than success, but amongst the failures are key pieces of data that suggest an anti-tumor immune response can be generated under the right conditions. Importantly, patients that have a functional immune system that can respond to the vaccine are more likely to generate an antitumor effect, and in several studies, the strength of the response correlates to the success of the vaccine. Although some trials have been successful, it is clear even from these trials that patients have a far lower T-cell response than what can be optimally generated, largely in part due to CD8 T-cell exhaustion caused by persistent exposure to tumor antigens. Now with new treatments approved to rescue exhausted CD8 T-cells by targeting CTLA-4 or PD1, and new drugs also being developed clinically and pre-clinically to achieve this, several opportunities are becoming available to improve the efficacy of antigen specific cancer vaccines.

Acknowledgements This work was supported by the following awards; H.T. Kissick: Department of Defense W81XWH-13-1-0246, Prostate Cancer Foundation Young Investigator Award, Winship Cancer Institute and Dunwoody Country Club/John Kaufmann Prostate Cancer Research Award. M.G Sanda: UO1-CA113913 and Prostate Cancer Foundation Mazzone Challenge Award. We would like to thank Dr Kathryn Pellegrini for editing and discussion.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010, 363:711-723.

2.

Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011, 364:2517-2526.

3.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K et al.: Safety and Current Opinion in Immunology 2015, 35:15–22

20 Vaccines

activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012, 366:2455-2465. 4.

Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS et al.: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013, 369:134-144.

5.

Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E et al.: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015, 372:320-330.

6.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB et al.: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012, 366:2443-2454.

7.

Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ et al.: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015, 372:311-319.

8.

Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL et al.: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014, 515:558-562.

9.

Hinrichs CS, Rosenberg SA: Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev 2014, 257:56-71.

10. Barrett DM, Singh N, Porter DL, Grupp SA, June CH: Chimeric antigen receptor therapy for cancer. Annu Rev Med 2014, 65:333-347. 11. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013, 368:1509-1518. 12. Porter DL, Levine BL, Kalos M, Bagg A, June CH: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011, 365:725-733. 13. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014, 371:1507-1517.

20. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006, 24:3089-3094. 21. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B et al.: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011, 364:2119-2127. 22. Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, Thatcher N, Wagstaff J, Zielinski C, Faulkner I et al.: Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol 2014, 11:509-524. 23. Vansteenkiste J, Zielinski M, Linder A, Dahabreh J, Gonzalez EE, Malinowski W, Lopez-Brea M, Vanakesa T, Jassem J, Kalofonos H et al.: Adjuvant MAGE-A3 immunotherapy in resected nonsmall-cell lung cancer: phase II randomized study results. J Clin Oncol 2013, 31:2396-2403. 24. ClinicalTrials.gov. National Library of Medicine (US). 2000–2015. Available from: https://clinicaltrials.gov/ct2/show/NCT00480025, NLM identifier: NCT00004451. 25. Ulloa-Montoya F, Louahed J, Dizier B, Gruselle O, Spiessens B,  Lehmann FF, Suciu S, Kruit WH, Eggermont AM, Vansteenkiste J et al.: Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol 2013, 31:2388-2395. Research identifying that patients with a pre-existing immune response to lung cancer have a better response to a MAGE-A3 vaccine. Exellent data supporting the hypothesis that an active immune system is more susceptible to manipulation by vaccination. 26. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R et al.: Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 2012, 18:1254-1261. 27. Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, Valone FH: Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 2000, 18:3894-3903. 28. ClinicalTrials.gov. National Library of Medicine (US) 2000–2015. Available from: https://clinicaltrials.gov/ct2/show/NCT00796445, NLM identifier: NCT00796445.

14. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991, 254:1643-1647.

29. Ozao-Choy J, Lee DJ, Faries MB: Melanoma vaccines: mixed past, promising future. Surg Clin North Am 2014, 94:1017-1030 viii.

15. Kissick HT, Sanda MG, Dunn LK, Arredouani MS: Immunization with a peptide containing MHC class I and II epitopes derived from the tumor antigen SIM2 induces an effective CD4 and CD8 T-cell response. PLoS One 2014, 9:e93231.

30. Sosman JA, Carrillo C, Urba WJ, Flaherty L, Atkins MB, Clark JI, Dutcher J, Margolin KA, Mier J, Gollob J et al.: Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. J Clin Oncol 2008, 26:2292-2298.

16. Kissick HT, Sanda MG, Dunn LK, Arredouani MS: Development of a peptide-based vaccine targeting TMPRSS2:ERG fusionpositive prostate cancer. Cancer Immunol Immunother 2013, 62:1831-1840.

31. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA,  Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K et al.: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013, 369:122-133. The first trial to combine anti-CTLA4 with anti-PD1 in any cancer. Stunning results in stage III and IV melanoma patients illustrating how well the immune system can fight cancer if the correct mechanisms are targeted.

17. Vigneron N, Stroobant V, Van den Eynde BJ, van der Bruggen P: Database of T cell-defined human tumor antigens: the 2013 update. Cancer Immun 2013, 13:15. 18. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW: Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009, 115:3670-3679. 19. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB et al.:  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010, 363:411-422. The third Phase III clinical trial of Provenge, but the first to set overall survival as the primary endpoint. The 2 previous trials had also found this outcome, but had progression free survival as the primary endpoint. These trials demonstrated that progression free survival was not always a useful indicator of immunotherapy success. The outcome of this research resulted in the first approval of any vaccine to treat cancer. Current Opinion in Immunology 2015, 35:15–22

32. Alanio C, Lemaitre F, Law HK, Hasan M, Albert ML: Enumeration of human antigen-specific naive CD8+ T cells reveals conserved precursor frequencies. Blood 2010, 115:3718-3725. 33. Pittet MJ, Valmori D, Dunbar PR, Speiser DE, Lienard D, Lejeune F, Fleischhauer K, Cerundolo V, Cerottini JC, Romero P: High frequencies of naive Melan-A/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals. J Exp Med 1999, 190:705-715. 34. Enk AH, Jonuleit H, Saloga J, Knop J: Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 1997, 73:309-316. 35. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP: Production of vascular endothelial growth factor by human tumors inhibits the www.sciencedirect.com

Therapeutic vaccines to treat cancer Kissick and Sanda 21

functional maturation of dendritic cells. Nat Med 1996, 2:10961103. 36. Gabrilovich DI, Nadaf S, Corak J, Berzofsky JA, Carbone DP: Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell Immunol 1996, 170:111-119. 37. Scarlett UK, Rutkowski MR, Rauwerdink AM, Fields J, EscovarFadul X, Baird J, Cubillos-Ruiz JR, Jacobs AC, Gonzalez JL, Weaver J et al.: Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J Exp Med 2012, 209:495-506. 38. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, Guillaume P, Luescher IF, Sander C, Ferrone S et al.: PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 2009, 182:5240-5249. 39. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM: Upregulation of Tim-3 and PD-1 expression is associated with tumor antigenspecific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010, 207:2175-2186. 40. Akondy RS, Monson ND, Miller JD, Edupuganti S, Teuwen D, Wu H, Quyyumi F, Garg S, Altman JD, Del Rio C et al.: The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J Immunol 2009, 183:7919-7930. 41. Miller JD, van der Most RG, Akondy RS, Glidewell JT, Albott S,  Masopust D, Murali-Krishna K, Mahar PL, Edupuganti S, Lalor S et al.: Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 2008, 28:710722. Excellent human vaccine immunology study characterizing the immune response to two of the most successful viral vaccines, YFVax against yellow fever and Dryvax against small pox. Key finding in this research was that up to 30% of the CD8 T-cells at the peak of the vaccine response are vaccine antigen specific. 42. Westermann J, Pabst R: Lymphocyte subsets in the blood: a diagnostic window on the lymphoid system? Immunol Today 1990, 11:406-410. 43. Gulley JL, Madan RA, Tsang KY, Jochems C, Marte JL, Farsaci B, Tucker JA, Hodge JW, Liewehr DJ, Steinberg SM et al.: Immune impact induced by PROSTVAC (PSA-TRICOM), a therapeutic vaccine for prostate cancer. Cancer Immunol Res 2014, 2:133141. 44. Kaufman HL, Wang W, Manola J, DiPaola RS, Ko YJ, Sweeney C, Whiteside TL, Schlom J, Wilding G, Weiner LM: Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2004, 22:2122-2132. 45. Fong L, Carroll P, Weinberg V, Chan S, Lewis J, Corman J, Amling CL, Stephenson RA, Simko J, Sheikh NA et al.: Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer Inst 2014:106. 46. Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM, Tsang KY, Poole DJ, Parnes HL, Wright JJ et al.: Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012, 13:501-508. 47. van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM, Gall HE, Harding TC, Jooss K, Lowy I 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 2012, 13:509-517. 48. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquee L, Trigo JM et al.: Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 2014, 15:59-68. www.sciencedirect.com

49. Golden EB, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC: The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2012, 2:88. 50. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM: Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993, 362:758-761. 51. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R: Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998, 188:2205-2213. 52. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006, 439:682-687. 53. Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S: FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer 2008, 8:57. 54. Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME et al.: PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014, 124:2246-2259. 55. Piao YR, Jin ZH, Yuan KC, Jin XS: Analysis of Tim-3 as a therapeutic target in prostate cancer. Tumour Biol 2014, 35:11409-11414. 56. Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG: Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 2009, 69:1694-1703. 57. Wu X, Zhang H, Xing Q, Cui J, Li J, Li Y, Tan Y, Wang S: PD-1(+) CD8(+) T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients. Br J Cancer 2014, 111:1391-1399. 58. Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen HR, Pyle KJ, Hipkiss E, Vignali DA, Pardoll DM, Drake CG: Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 2009, 182:6659-6669. 59. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, Anders R, Netto G, Getnet D, Bruno TC et al.: LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 2007, 117:3383-3392. 60. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, Bettini ML, Gravano DM, Vogel P, Liu CL et al.: Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012, 72:917-927. 61. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA: Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol 2004, 172:5450-5455. 62. Romano E, Michielin O, Voelter V, Laurent J, Bichat H, Stravodimou A, Romero P, Speiser DE, Triebel F, Leyvraz S et al.: MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial. J Transl Med 2014, 12:97. 63. Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR: Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 2009, 83:9122-9130. 64. Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM et al.: Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 2008, 205:2763-2779. 65. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC: Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010, 207:2187-2194. Current Opinion in Immunology 2015, 35:15–22

22 Vaccines

66. Fourcade J, Sun Z, Pagliano O, Chauvin JM, Sander C, Janjic B, Tarhini AA, Tawbi HA, Kirkwood JM, Moschos S et al.: PD-1 and Tim3 regulate the expansion of tumor antigen-specific CD8(+) T cells induced by melanoma vaccines. Cancer Res 2014, 74:1045-1055. 67. Ibrahim NK, Murray JL, Zhou D, Mittendorf EA, Sample D, Tautchin M, Miles D: Survival advantage in patients with metastatic breast cancer receiving endocrine therapy plus

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sialyl Tn-KLH vaccine: post hoc analysis of a large randomized trial. J Cancer 2013, 4:577-584. 68. Miles D, Roche H, Martin M, Perren TJ, Cameron DA, Glaspy J, Dodwell D, Parker J, Mayordomo J, Tres A et al.: Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer. Oncologist 2011, 16:1092-1100.

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The role of active vaccination in cancer immunotherapy: lessons from clinical trials.

In the past few years, a number of different immunotherapeutic strategies have shown impressive results in cancer patients. These successful approache...
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