3.1.1 Antagonistic Antibodies: Blocking the Suppre...
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.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.This positive result has been subsequently validated in another randomized Phase III clinical trial of patients with metastatic melanoma treated with dacarbazine and ipilimumab.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 [21-23].
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.Indeed,pseudo-tumor progressions due to the immune infiltration of the tumor upon anti-CTLA4 therapy could mislead to a disease progression.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.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).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).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 [24, 25].(https://www.daowen.com)
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, NewYork, 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).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 immune mediated IFNg exposure.Another anti-PD-1 mAb (lambrolizumab, now called pembrolizumab, developed by Merck Sharp & Dohme, White House Station, NJ, USA) has also shown very promising results in a Phase I trial of patients with melanoma with an objective response rate (ORR) of 38%.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.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.Also, anti-PD-L1 mAbs seem to have lower lung toxicity profile than anti-PD-1 mAbs.Together, anti-PD-1 and anti-PD-L1 antibodies have shown significant activity (20%-50%ORR)when used as a monotherapy in early phase trials in many metastatic cancer types such as melanoma, non-small cell lung cancers (NSCLC), bladder, renal cell cancer, and Hodgkin lymphoma [10, 26, 27].
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.The concomitant therapy group had a better ORR than the sequenced regimen 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 ipilimumab nivolumab 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.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.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 54-99, 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.Anti-PD-L1 therapy has demonstrated a 50%response rate in PD-L1 positive metastatic bladder cancer patients.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.Other mAbs targeting immunosuppressive molecules such as BTLA (B- and Tlymphocyte attenuator, CD272), TIM3 (T-cell immunoglobulinmucin-3), or VISTA (V-domain immunoglobulin suppressor of T cell activation),are currently under preclinical development [10, 28].