Pediatr Blood Cancer 2015;62:1317–1325

REVIEW Tumor-Targeted and Immune-Targeted Monoclonal Antibodies: Going From Passive to Active Immunotherapy Aur
elien Marabelle,

MD, PhD,

Monoclonal antibodies (mAbs) have inaugurated the concepts of tumor-targeted therapy and personalized medicine. A new family of mAbs is currently emerging in the clinic, which target immune cells rather than cancer cells. These immune-targeted therapies have recently demonstrated long-term tumor responses in adults with refractory/relapsing metastatic solid tumors. Pediatric cancers are

Key words:

and Juliet Gray,

MBBS, PhD

3

*

different from their adult counterparts in terms of histological features and immune infiltrates. However, the same immune checkpoint targets can be expressed within the microenvironment of pediatric tumors. The benefits of immune checkpoint blockade in pediatric cancers are currently under evaluation in early phase clinical trials. Pediatr Blood Cancer 2015;62:1317–1325. # 2015 Wiley Periodicals, Inc.

anti-CTLA-4; anti-PD-1; anti-PD-L1; immune checkpoint blockade; monoclonal antibodies; pediatric cancers

INTRODUCTION Over the last 20 years, major improvements have been made in the design and production of mAbs and they are now used as passive immunotherapy strategies as part of the standard treatment of many cancers, targeting surface antigens expressed by tumor cells (e.g., HER2, EGFR). More recently, it has been demonstrated that mAbs could be used to generate active antitumor immunity in patients with cancer, by targeting costimulatory or inhibitory molecules expressed at the surface of immune cells. Such immunomodulatory mAbs may be either agonistic, targeting co-stimulatory molecules, or antagonistic, “blocking” inhibitory molecules. The aim of these approaches is to augment endogenous anti-tumor immune responses, either by providing direct immune stimulation or by releasing regulatory mechanisms. They have resulted in a paradigm shift in cancer therapy, where instead of using drugs to target the tumor cells, molecules are designed to target the immune system in order to break the tumor tolerance, and stimulate the anti-tumor immune response. The promising results obtained with such immunomodulatory mAbs in early phase clinical trials open many perspectives for synergistic combinatorial strategies.

TUMOR-TARGETED MONOCLONAL ANTIBODIES FOR PERSONALIZED MEDICINE IN ONCOLOGY Using Tumor Targeting Monoclonal Antibodies as Passive Cancer Immunotherapy In 1982, Levy and co-workers demonstrated that tumor responses could be obtained in patients with nonHodgkin lymphoma after administration of a monoclonal antibody designed to target the idiotype of their B-cell malignancy [1]. Subsequently, the strategy was simplified and CD20, an antigen commonly expressed by B-cells, was chosen as universal target of B-cell lymphomas. The antibody generated against CD20, called rituximab, became the first monoclonal antibody to gain FDA approval for the treatment of cancer. Since then, many other mAbs have been developed as passive immunotherapy strategies in oncology, targeting either an antigen expressed at the surface of tumor cells or targeting a growth factor (VEGF) involved in the vascularization of tumors. All types of antigens could be in theory targeted by antibodies, including nonpeptidic ones such as  C

1,2

2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25508 Published online 21 March 2015 in Wiley Online Library (wileyonlinelibrary.com).

gangliosides. Recently, it has been demonstrated in a Phase III randomized trial that a mAb targeting the ganglioside GD2 could improve the survival of children with high-risk neuroblastoma [2]. The results of this trial have fueled the development of anti-tumor monoclonal antibodies in pediatric oncology, but with a significant delay compared to their FDA/EMA first approval in adults (Fig. 1).

Mechanisms of Action of Tumor Targeting Antibodies The mode of action of mAbs is complex and potentially involves multiple mechanisms. Some antibodies, such as rituximab, may have a direct cytotoxic effect by inducing apoptosis of the tumor cells after ligation to the targeted molecules expressed at their surface. Monoclonal antibodies can also be used as antagonists of tumor growth factors, blocking either the ligands or their cognate receptor, such as bevacizumab targeting VEGF, or trastuzumab targeting the HER2 receptor expressed by some breast cancers. Once mAbs are bound to their cognate antigen expressed at the surface of tumor cells, their distal part, the so called Fc domain, can trigger destruction of the targeted cell by engagement of host immune effector mechanisms. This may include activation of the cytotoxic enzymes of the complement cascade (CDC or Complement Dependent Cytotoxicity). It may also trigger the cytotoxic effect of innate immune cells such as NK (natural killer) cells via the activation of their Fc receptors (ADCC or Antibody Dependent Cellular Cytotoxicity). Finally, it can induce cell killing via the activation of phagocytosis by monocytes/macrophages (ADCP or Antibody Dependent Cellular Phagocytosis) [3] (Fig. 2). 1

Institut d’ H
ematologie et d’Oncologie P
ediatrique, Centre de Lutte contre le Cancer L
eon B
erard, Lyon, France; 2Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France; 3Antibody and Vaccine Group, Cancer Research UK Experimental Cancer Medicine Centre, Faculty of Medicine, University of Southampton, Southampton, United Kingdom Conflict of interest: Dr. Marabelle has received honorarium and consultancy fees from Amgen, BMS, and Roche/Genentech.


Correspondence to: Aur
elien Marabelle, Clinical Director, Cancer
Immunotherapy Program, 114, rue Edouard-Vaillant, 94805 Villejuif Cedex, France. E-mail: [email protected] Received 31 December 2014; Accepted 3 February 2015

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Fig. 1. FDA-approved monoclonal antibodies in oncology. In red: the recently approved immune checkpoint blockade antibodies. Specificities: rituximAb: anti-CD20; trastuzumab: anti-HER2; gemtuzumab ozogamicin: anti-CD33; alemtuzumab: anti-CD52; ibritumomab tiuxetan: antiCD20; tositumomab: anti-CD20; cetuximAb: anti-EGFR; bevacizumab: anti-VEGFR; panitumumab: anti-EGFR; ofatumumab: anti-CD20; denosumab: anti-RANKL; brentuximAb veodtin: anti-CD30; ipilimumab: anti-CTLA4; pertuzumab: anti-HER2; obinutuzumab: anti-CD20; antiHER2; ofatumumab: anti-CD20; ramucirumab: anti-VEGFR2; siltuximAb: anti-IL6; pembrolizumab: anti-PD-1.

New Generations of Tumor-Targeting Monoclonal Antibodies One of the first limits in mAbs development has been their intrinsic immunogenicity. Indeed, the first generations of mAbs were produced in human/murine hybridomas, resulting in chimeric mAbs which could themselves be recognized as a foreign antigen and eliminated by the host immune system via human anti-murine

antibodies (HAMAs). For this reason, the new generations of mAbs have been fully humanized, resulting in significantly reduced immunogenicity and low levels of human anti-human antibodies (HAHAs). The degree of humanization of mAbs is specified in their name (Fig. 3). The role of Fc-mediated cancer cell death has been demonstrated in retrospective studies showing the prognostic value of Fc receptors polymorphisms in patients treated by anti-tumor

Fig. 2. Monoclonal antibodies are versatile platforms for tumor-targeted therapies. Illustration of the mechanisms of action of commonly used mAbs. Pediatr Blood Cancer DOI 10.1002/pbc

Tumor- and Immune-Targeted Monoclonal Antibodies

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Fig. 3. Nomenclature for monoclonal antibodies: all is in the name.

mAbs [4], including in children with neuroblastoma treated with anti-GD2 mAb [5]. Therefore, new anti-tumor antibodies are now designed to have an isotype with good affinity for Fc receptors and with a glycosylation status that enhances their ADCC ability, for example the obinutuzumab (also called GA101), a defucosylated anti-CD20 mAb approved by the FDA in 2013 for the treatment of chronic lymphocytic leukemia. Thanks to their ability to target specifically tumor antigens, mAbs are now also used as versatile platforms for the specific delivery of cytotoxic drugs to cancer cells. Indeed mAbs can be linked to a molecule of chemotherapy, for example, the anti-CD33 gemtuzumab ozogamicin (Mylotarg*) currently developed in Acute Myeloid Leukemia or the new anti-CD30 brentuximAb vedotin (Adcetris*) currently in clinical trial for anaplastic lymphoma and Hodgkin Disease. Monoclonal antibodies can also be used to deliver in situ radioactive molecules, such as 90Y-Ibritumomab (Zevalin*), a modified anti-CD20 antibody used nonHodgkin lymphomas (Fig. 2).

IMMUNE TARGETED ANTIBODIES: TARGETING IMMUNE CELLS RATHER THAN CANCER CELLS The very nature of “passive” immunotherapy means that the immunity is transient, and lasts only as long as the mAb survives in the patients. Targeting the immune system per se offers the attraction of potentially generating active and long-lasting anti-tumor immunity. Furthermore, since individual tumor antigens are not targeted, such mAb are not tumor or patient specific, and potentially achieve broad, polyclonal antitumor immunity, directed against multiple tumor antigens and reducing the chances of immune escape.

Breaking the Tumor Immune Tolerance The major discovery which allowed understanding better the tolerance of cancer cells by the immune system happened in fields not linked to oncology. In 2001, three research teams published back-to-back in Nature Genetics the identification of a gene called FOXP3 (forkhead box P3) which, when mutated, was responsible in humans for a neonatal dys-immune disease called the IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) and in mice for a spontaneous auto-immune model (scurfy phenotype) [6–8]. Shortly, after two other teams published that the transcription factor FOXP3 was involved in the development and function of a subset of immunosuppressive CD4þ T-cells called regulatory T-cells or Tregs [9,10]. The ability to specifically Pediatr Blood Cancer DOI 10.1002/pbc

identify this Treg population thanks to the expression of FOXP3 has made possible the development of studies on the phenomenon of immune tolerance in the tumor micro-environment. Subsequently, it has been shown that the level of Treg infiltration into solid tumors was a factor of bad prognosis for the survival of patients in multiple types of cancers [11]. One mode of action of Tregs is to inhibit the activation of immune cells via direct cell–cell interactions. A major molecule expressed by Tregs and playing the role of an immunosuppressing interaction is called CTLA-4 (Cytotoxic TLymphocyte Antigen 4), also known as CD152 [12,13]. Therefore, blocking CTLA-4 via an antibody interferes with the ability of Tregs to perform immunosuppression. Another important immunosuppressive molecule which could be expressed by Tregs but also other CD4þ and CD8þ T-cells is called PD-1 (Programmed Death1) [14]. Its ligand, PD-L1, inhibits the cytotoxic function of antitumor PD-1pos lymphocytes when it is expressed at the surface of tumor cells. However, PD-L1 can also be expressed on many other cell types in the tumor microenvironment such as tumor infiltrating fibroblasts, macrophages, Tregs, dendritic cells (DCs), and activated T-cells [15]. Both CTLA-4 and PD-1 receptors transmit inhibitory signals to T-cells upon stimulation by their ligands in the immunological synapse with antigen presenting cells. Many preclinical studies have demonstrated that antibodies targeting CTLA4, PD-1, or PD-L1 can generate potent anti-tumor immune responses and cure tumor bearing mice [16].

Antagonistic Antibodies: Blocking the Suppressors Because of the positive results obtained in murine tumor models, academic teams, and pharmaceutical companies have initiated the clinical development of these immunomodulatory mAbs in patient with cancers [16,17]. The clinical proof of concept was achieved with the anti-CTLA-4 mAb, ipilimumab, developed by Bristol– Myers Squibb (BMS). In a randomized phase III trial published in 2010, it was demonstrated that ipilimumab monotherapy induced long-term survival in 20% patients with refractory or relapsing metastatic melanoma [18]. This positive result has been subsequently validated in another randomized Phase III clinical trial of patients with metastatic melanoma treated with dacarbazine  ipilimumab [19]. Whereas directly targeting anti-tumor antibodies have limited access to the central nervous system because of the blood brain barrier, interestingly, the anti-tumor immune response generated upon ipilimumab therapy have in instances been seen to eradicate disease from metastatic sites all over the body, including in the brain [20,21].

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Probably linked to its new mode of action, ipilimumab therapy induces uncommon patterns of tumor responses which required the development of new radiological assessment criteria [22]. Indeed, pseudo-tumor progressions due to the immune infiltration of the tumor upon anti-CTLA4 therapy could mislead to a disease progression [23]. Anti-CTLA-4 therapy efficacy relies on a T-cell mediated anti-tumor immune response in mice. Interestingly, having less of 1,000 lymphocytes per mm3, especially after the first and second course of ipilimumab, has been associated to a worse outcome of patient with metastatic melanoma [24]. Although the response rates for ipilimumab are relatively modest, dramatic responses have been observed, and when responses are observed they tend to be durable (up to 10 years) [25]. This result is in contrast with BRAF inhibitor tumor-targeted therapy in patients with BRAF-mutated melanoma patients who presented more than a 50% response rate but all subsequently relapsed and therefore presented little benefits in long-term overall survival (OS) [26]. However, ipilimumab therapy showed a significant, and unknown in oncology, toxicity profile, with about 60% of patients developing auto-immune symptoms, one third being of grade 3–4 (Table I) [18]. The therapeutic potential of immunomodulatory mAbs as anticancer agents has been confirmed with the exciting positive results of the phase I clinical trial of the anti-PD-1 antibody nivolumab (developed by Bristol Myers Squibb, BMS, New York, NY, USA) in patients with several types of solid tumors. Nivolumab monotherapy showed tumor responses in patients with metastatic

melanoma but also in patients with renal cell cancers (RCC) and non-small cell lung cancers (NSCLC) [27]. In this study, they found that all the patients who responded to anti-PD-1 monotherapy had PD-L1 expressed in their tumor. This result suggested that the PDL1 level of expression in the tumors of patients could be predictive of the response to the anti-PD-1 therapy. However, other studies have reported some responses in patients without PD-L1 expression in their tumor. This discrepancy is explained by the fact that PD-L1 expression is a dynamic phenomenon happening upon immunemediated IFNg exposure [28]. Another anti-PD-1 mAb (lambrolizumab, now called pembrolizumab, developed by Merck Sharp & Dohme, White House Station, NJ, USA) has also shown recently very promising results in a Phase I trial of patients with melanoma with an objective response rate (ORR) of 38% (Table II) [29]. Interestingly, three mAbs targeting the ligand (PD-L1) rather than the receptor (PD-1) have also been developed: one by BMS (BMS-936559), another one by Genentech (MPDL3280A), the third one by MedImmune/Astrazeneca (MEDI 4736). All three have shown promising results in early phase clinical trials [30,31]. In comparison to anti-CTLA-4, anti-PD-1, and anti-PD-L1 mAbs have shown lower toxicity profiles and higher response rates when used in monotherapy in patients with metastatic melanoma (Table II). Also, anti-PD-L1 mAbs seem to have lower lung toxicity profile than anti-PD-1 mAbs [31]. Together, anti-PD-1 and anti-PD-L1 antibodies have shown significant activity (20–50%

TABLE I. Examples of On- and Off-target Toxicities of Monoclonal Antibodies

Symptoms Infusion immediate reaction, hypotension, urticarial, nausea, dyspnea

Tumor lysis syndrome

Skin rashes, diarrhea Skin rashes, diarrhea, hepatitis, pneumonitis, endocrine disorders

Target

Monoclonal Antibodies

Treatment

Off-target effects

Any, in theory

Stop perfusion

Anaphylactic (IgE mediated) or anaphylactoid (mastocytes mediated) reactions

Incidence higher in murine > chimeric > humanized > fully human mAbs

Anti-histaminic drugs

On-target effect

Tumor-targeted antibodies Large Tumor Burden EGFR

Immune Checkpoint Blockades CTLA-4, PD-1, PD-L1

Especially in hematological malignancies (e.g., rituximab, alemtuzumab, …)

Acetaminophen(paracetamol) Steroids  epinephrin Resume perfusion if moderate symptoms but slow down perfusion debit. Hyper-hydration

rasburicase

panitumumab, cetuximab,…

Ipilimumab, nivolumab, pembrolizumab

Topical clindamycin & hydrocortisone  oral minocycline Steroids

 infliximab Pediatr Blood Cancer DOI 10.1002/pbc

Pediatr Blood Cancer DOI 10.1002/pbc

Fully Human IgG1

Fully Human IgG1

Fully Human IgG2

Fully Human IgG4

Fully Human IgG4 Fully Human IgG4

Fully Human IgG1 (engineered to avoid NK ADCC)

Fully Human IgG1 & IgG4

Anti-CTLA-4 (ipilimumab)

Anti-CTLA-4 (ipilimumab)

Anti-CTLA-4 (tremelimumab)

Anti-PD-1 (nivolumab)

Anti-PD-1 (pembrolizumab) Anti-PD-L1 (BMS-936559)

Anti-PD-L1 (MPDL3280A)

Anti-CTLA-4 & Anti-PD-1 (ipilimumab & nivolumab) BMS/ Medarex/ Ono Pharma

Genentech

BMS

MSD

Pfizer/ Medimmune/ AstraZeneca BMS/ Medarex/ Ono Pharma

BMS

BMS

Company

Phase I NCT01024231 Concurrent Regimen Group

Phase NCT01375842 I

Phase I NCT01295827 Phase I NCT00729664

Phase I NCT00730639

Phase III NCT00094653 (3 mg/kg) Phase III NCT00324155 (10 mg/kgþDTIC) Phase III NCT00257205

9/52 (17%) 2/17 (12%) 5/49 (10%) 1/17 (6%) 11/38 (29%) 6/47 (13%)

9/41 (22%) 21/52 (40%)

RCC NSCLC Ovarian Melanoma RCC

NSCLC Melanoma

9/33 (27%) 14/76 (18%) 44/117 (38%)

RCC NSCLC Melanoma Melanoma

26/94 (28%)

36/328 (10%)

38/203 (15.2%)

15/137 (10.9%)

PRþCRa

Melanoma

Melanoma

Melanoma

Melanoma

Tumors

139/247 (56.2%)b

30%

46% ND

53%

53% 31% 22% 43%

42%

56% 26% ND

41%

28/53 (53%)

22/171 (13%)d

19/207 (9%)

17/135 (13%)

41/296 (14%)

170/325 (52%)

30/131 (23%)

20%

ND

Grade 3–4 drug toxicity

PFS at 24 weeks

17/53 (32%)

4/171 (2%)e

5/207 (2%)

0/53 (0%)

0/171 (0%)

0/207 (0%)

0/135 (0%)

3/296 (1%)

7/296 (2%)e

6/135 (4%)e

7/325 (2%)

0/247 (0%)

2/131 (1.5%)

Drug related death

84/325 (26%)

103/247 (42%)

19/131 (14.5%)

Immune related grade 3–4 toxicity

(Wolchok et al., 2013)

(Herbst et al., 2013)

(Hamid et al., 2013) (Brahmer et al., 2012)

(Topalian et al., 2012)

(Ribas et al., 2013)

(Robert et al., 2011)

(Hodi et al., 2010)

Ref

a all doses for the phase I trials. DTIC: dacarbazine. ND: Not determined. bto be compared to the Grade 3-4 adverse event rate of DTIC control group alone which was 69/251 (27.5%). c to be compared to the Immune related Grade 3-4 adverse event rate of DTIC control group alone which was 15/251 (6%). dNo dose limiting toxicity found. ebased on the grade 3–4 toxicity on skin (pruritus, rash, vitiligo), digestive tract (colitis/diarrhea, pancreatitis), liver (ALT), nervous system (Myasthenia gravis) immune system (lymphopenia, sarcoidosis), and endocrine disorders (thyroid, adrenal).

Type

imAb (name)

Trial type NCT # (dose)

TABLE II. Efficacy of Immunomodulatory mAbs in Patients With Solid Tumors (Published Data)

Tumor- and Immune-Targeted Monoclonal Antibodies 1321

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ORR) when used as a monotherapy in early phase trials in many metastatic cancer types such as melanoma [29,32], non-small cell lung cancers (NSCLC) [31], bladder [33], renal cell cancer [34], and Hodgkin lymphoma [35]. Recently, a combination strategy of anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) has been tested in a phase I trial of patients with advanced melanoma, either in a sequential fashion (ipilimumab followed by nivolumab) or concomitantly [36]. The concomitant therapy group had a better ORR than the sequencedregimen group (40% vs. 20%, respectively). Notably, in the concurrent-regimen group, the patients who were treated at ipilimumab 3 mg/kg and nivolumab 1 mg/kg showed a 53% ORR, all with tumor responses of 80% or more. Response rates such as this are unprecedented for immunotherapies, and are particularly impressive given the advanced disease state and poor prognosis if this trial population. Although the incidence of adverse events was higher in the ipilimumabþnivolumab combination (53% of grade 3 or 4) than with each drug used in monotherapy (20% for ipilimumab alone; 15% for nivolumab alone), but these events, notably auto-immune symptoms, were qualitatively equivalent to those obtained with each drug in monotherapy. Two interesting features came out of this early phase combination trial. First, tumor regressions were generally faster and more marked compared to the monotherapy trials [36]. Second, neither the PD-L1 expression in the tumor, nor the absolute lymphocyte count appeared to be predictive markers of tumor response in the context of the combination therapy [37].

A common feature of these mAb is that they generally appear to provide long lasting tumor regressions in those patients who respond. In 2012, Prieto and co-workers published a retrospective analysis of three ipilimumab clinical trials in patients with metastatic melanoma. First, the complete response rates turned out to be eventually higher than in the primary clinical reports because some patients became complete responders months to years after the completion of the trial. At the time of this retrospective analysis, the complete response rate (CR) was around 6% in the two protocols testing ipilimumab as a monotherapy and of 17% in the third trial which combined IL-2 to ipilimumab. Second, 14 out of 15 complete responders were still having a CR ongoing at 54þ to 99þ months, despite cessation of therapy. This suggests that some of these very high-risk patients have been cured by the therapy. Anti-PD-1 and anti-PD-L1 monotherapies have also shown significant anti-tumor activity in refractory/relapsing metastatic lung cancers and renal cell cancer (Table II). Recently, anti-PD-L1 therapy has demonstrated a 50% response rate in PD-L1 positive metastatic bladder cancer patients [33]. Therefore, antagonistic mAbs can induce significant tumor response rates in aggressive metastatic cancers, provide long-term survival in some patients and show synergistic activity upon combination. These features make this new class of anti-cancer drugs very promising for the near future. Other mAbs targeting immunosuppressive or costimulatory molecules are currently under development (Table III). Other mAbs targeting immunosuppressive molecules such as BTLA (B- and Tlymphocyte attenuator, CD272), TIM3 (T-cell immunoglobulin

TABLE III. New Immunomodulatory mAbs Currently in Early Phase Trials ismAb Anti-KIR lirilumab (IPH2102) lirilumab þ ipilimumab lirilumab þ nivolumab elotuzumab þ lirilumab or þ urelumab Anti-CD137 urelumab (BMS-663513) urelumab þ cetuximab urelumab þ nivolumab urelumab þ rituximab Anti-OX40 aOX40 þ Stereotactic Body Radiation aOX40 þ cyclophosphamide þ radiation MEDI6383 RG7888 (anti-OX40, MOXR0916) Anti-LAG3 BMS-986016 BMS-986016  nivolumab Anti-CD40 BMS-986090 Anti-CD27 Varlilumab (CDX-1127) Anti-B7H3 MGA271

Company

Status

NCT #

Completion

Innate Pharma /BMS

Phase 2 Phase 1 Phase 1 R-Phase 1

NCT01687387 NCT01750580 NCT01714739 NCT02252263

Jun 2016 Oct 2016 Sep 2017 Apr 2017

Acute Myeloid Leukemia Cancer NOS Cancer NOS Multiple Myeloma

NCT01471210 NCT02110082 NCT02253992 NCT01775631

Mar 2019 Jan 2017 Dec 2018 Feb 2017

Solid Tumors/B-Cell NHL CRC, HNSCC Solid Tumors/B-cell NHL B-Cell Malignancies Mþ Breast Cancer; MþLung; Mþ Liver Prostate Cancer

BMS

Phase Phase Phase Phase

1 1 1 1

Tumors

Providence Health & Services

Phase 1/2

NCT01862900

Feb 2023

Phase 1/2

NCT01303705

Oct 2015

MedImmune/AZ

Phase 1

NCT02221960

Aug 2018

Roche/Genentech

Phase I

NCT02219724

Aug 2018

Bladder Cancer, CRC, NSCLC, HNSCC Solid Cancers

BMS

Phase 1 Phase 1

NCT02061761 NCT01968109

Jun 2018 May 2018

Hematologic Neoplasms Solid Cancers

BMS

R-Phase 1

NCT02079480

Apr 2015

Healthy Volunteers (R vs. Placebo)

Celldex

Phase 1

NCT01460134

Mar 2015

B&T-cellLymphomas, Solid Tumors

MacroGenics

Phase 1

NCT01918930

Mar 2014

Melanoma

Elotuzumab is directed against CS1, a cell surface glycoprotein that appears highly expressed on myeloma cells. Pediatr Blood Cancer DOI 10.1002/pbc

Tumor- and Immune-Targeted Monoclonal Antibodies mucin-3), or VISTA (V-domain immunoglobulin suppressor of Tcell activation), are currently under pre-clinical development [16].

Agonistic Antibodies: Activating the Effectors As above mentioned, mAbs have been so far essentially designed to block receptors (antagonistic function) or to induce the death of the cells targeted. Another potential mechanism that may be exploited to generate therapeutic tumour immunity is the ability of some mAbs to behave as surrogate ligands, providing agonistic signals to immunostimulatory receptors. This is the case for urelumab, an anti-CD137 mAb developed by BMS which is currently being tested in solid tumors and lymphoma (Table III). CD137 (also known as 4-1-BB) is a co-stimulatory receptor expressed on the membrane of activated T- and NK-cells. The ability of agonistic anti-CD137 mAb, either alone or in combination, to generate anti-tumor immune responses is currently being explored in clinical trials (Table III). Another agonistic mAb targeting the costimulatory molecule CD134 (a.k.a OX40) is currently tested in phase I/II clinical trials in combination with radiation therapy for patients with metastatic breast cancer and in combination with radiation and chemotherapy in metastatic prostate cancer (Table III). Other agonistic mAbs are under early development targeting costimulatory molecules such as HVEM (herpesvirus entry mediator, aka Tumor necrosis factor receptor superfamily member 14 or TNFRSF14), CD27 and GITR (glucocorticoid-induced tumor necrosis factor receptor) [16].

IMMUNE CHECKPOINT THERAPY IN PEDIATRIC CANCERS Numerous reports have shown that pediatric hematological malignancies and pediatric solid tumors are sensitive to passive (anti-tumor mAbs) or adoptive (allogenic hematopoietic stem cell transplantation, allogenic donor lymphocyte infusions, anti-tumor CTLs, CARs, …) immunotherapy [2,38–43]. So far, active immunotherapy strategies based on tumor vaccines have failed to induce significant levels of anti-tumor activity in patients, probably because they do not address sufficiently the issue of tumor antigen immune tolerance. However, some pre-clinical rationale in pediatric tumor models support the idea that pediatric tumors could benefit from vaccines in combination with immune checkpoint blockade [44]. Interestingly, cancers showing patterns of response upon CTLA4 or PD-1/PD-L1 blockades in adults are cancers with high levels of somatic point mutations: melanoma, non-small cell lung cancer, renal cell cancer, bladder cancer, … [45]. One hypothesis to explain this phenomenon is that these cancers have a higher rate of tumor neo-antigens that could be recognized by immune cells. This hypothesis is supported by the fact that lung cancers from smoking patients, who have a higher rate of somatic DNA mutations, also have a better response rate to PD-1/PD-L1 blockade therapy than non-smoking patients with lung cancer (Horn L, abstract #MO18.01, IASLC 2013). This is also supported by the recent data highlighting the link between somatic point mutations, neoantigens and long term responses to anti-CTLA4 in metastatic melanoma [46]. This could be an argument against the use of immune checkpoint blockade therapy in pediatric cancers who classically present with a low rate of somatic point mutation in their cancer cells, and a variable rate of gene/chromosome copy number Pediatr Blood Cancer DOI 10.1002/pbc

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alterations [47–49]. However, this general rule may not apply to all pediatric cancers and to all stages. Indeed, children with a high-risk neuroblastoma present a significantly higher somatic point mutation rate than low-risk ones [50], and some pediatric tumor genomes can present focally a very high level of chromosome rearrangement rate (so-called chromothripsis) [51]. These patients should have a higher rate of tumor-associated neoantigens, and therefore may be more immunogenic and indeed endogenous antitumor T-cells responses are documented in these patients [52]. Also, the sensitivity to PD-1/PD-L1 immune checkpoint blockade in adult patients seem closely linked to the level of expression of PDL1 in the tumor micro-environment and the level of T-cell immune infiltrates [27,28,53,54]. Besides cancer cell histology, one of the major differences between adult and pediatric cancers is the type of tumor immune infiltrates. Adult cancers have predominantly dendritic cell and T-cell immune infiltrates, and these infiltrates are prognostic in many cancers. As opposed to adult cancers, Pediatric tumors show little infiltrates by T-cells and DCs but have high levels of tumor-associated macrophages (TAMs) and myeloid cells [55], and the level of TAMs also has a prognostic value in neuroblastoma [56], Ewing tumors [57], and osteosarcoma [58]. These nosologic differences could also argue against the fact that immune checkpoint blockade could not work in Pediatric cancers. However, PD-L1 can be highly expressed in some pediatric tumor histologies, notably on cancer cells and TAMs, and therefore can hamper the development of an anti-tumor T-cell response [59,60]. Indeed, PD-L1 expression has been demonstrated in Wilms [61,62], Hodgkin disease [63–65], nonHodgkin B- and T-cell lymphomas [66–69], notably Anaplastic lymphomas [65,69,70], Glioblastoma [71–73], RMS [74], but also on TAMs [72,75,76]. A phase I study of anti-CTLA-4 monotherapy (ipilimumab) has been recently completed in children with relapsing/refractory solid tumors and showed stable disease as the best response in 5/21 (24%) of various types pediatric cancer histologies [77]. A multi-center phase II trial for children aged 12-18 y.o is currently run by BMS in children with metastatic melanoma (NCT NCT01696045). AntiPD-1 antibodies from BMS (nivolumab) and Merck (pembrolizumab) are now approved by the FDA for the treatment of adult metastatic melanoma in the USA. They are currently accessible through national access programs in Europe for patients with ipilimumab refractory metastatic melanoma, including children above 12 y.o. Also, anti-PD-1 and anti-PD-L1 trials for pediatric solid tumors should be started in the upcoming year in Europe and the USA.

UNSOLVED ISSUES AND REMAINING QUESTIONS There is now substantial evidence that the immune system plays a role in tumor response to conventional chemotherapies [78]. However, the successive myeloablative chemotherapy regimens received by cancer patients eventually hamper the ability of the immune system to fight cancer cells. The role played by the immune system upon radiotherapy is also well described now, but it is limited to the irradiated fields and do not allow the control of distant, un-irradiated, metastatic tumor sites [79]. Tumor-targeted therapies such as kinase inhibitors and tumor-targeted mAbs enable the generation of systemic tumor responses with limited hematologic toxicities. However, their efficacy is limited in time due to the emergence of subclones with target loss. Clinically, this translates into longer median progression-free survivals, but not in improved

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OS. The pre-clinical rationale built over the last 15 years in murine syngeneic tumor models strongly suggest that the combination of tumor- and immune-targeted therapies could synergize to improve both the ORR and the OS in cancer patients [80]. However, early phase clinical trials have recently shown that such combination strategies could be highly toxic for patients [36,81,82]. This issue underscores the need to find predictive markers of response to limit the exposition of patients to non-beneficial toxicity. Also, understanding better the mechanism of action of these drugs could allow us to better manage or hamper their toxicity profile. Like before with conventional therapies, we will learn how to manage the toxicity generated by immunomodulatory mAbs, especially if they improve the OS of our patients.

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