Cancer immunotherapy is an approach of treating cancer by harnessing the potential of body’s own immune system. After decades of initial disappointments in the area, the tide has finally changed with some recent successes in clinical trials. The strategy that received clinical validation targets immune suppressingsignaling pathways in the tumor microenvironment, and raises the overall tumor specific T cell populations to fight tumors. Antibodies such as Ipilimumab, Nivolumab, Durvalumab, and Pembrolizumab were developed to target immunosuppression signaling pathways and are now approved by FDA for treating patients suffering from various cancers.In addition to these antibodies, adoptive T cell therapy that engineerpatient’s T cells to fight their cancers is showing a great promise in theclinical trials and is being actively pursued to treat cancers.The success of these approaches has cemented cancer immunotherapy potential in patients and even swayed away skeptics.
Ipilimumab is a monoclonalantibody that inhibits cytotoxic T lymphocyte antigen (CTLA-4) that is expressed on surface of activated T cells to inhibit their activtion. CTLA-4 inhibits activated T cells through inhibition of CD28 dependent T cell co-stimulation, a process that is crucial for T-cell activation in response to an antigen. This mechanism of immunosuppression was first elucidated by James Allison from MD Anderson Cancer Institute at USA. In brief, CTLA-4 on T cells interacts with B7 family of accessory molecules expressed on tumor antigen presenting cells (APC), and prevents the typical T cell activation signals between B7 of tumor APC and CD28 of T cells. The interaction of CTLA-4 with B7 is inhibitory in nature and blocks the further activation and expansion of T cells, and thus effectively control the activation of tumor antigen specific T cells. Ipilimumab by targeting the CTLA-4 antigen, relieves these negative signaling mechanisms leading to activation and expansion of tumor antigen specific T cells to fight tumor cells.
Ipilimumab is found to be effective against patients suffering from late stage metastatic melanoma. Phase III clinical trials with Ipilimumab reported a median survival rate of 10.1 months in unresectable stage III and IV melanoma patients treated with Ipilimumab and glycoprotein 100 peptide vaccine relative to 6.1 month survival of patients receiving control glycoprotein 100 peptide vaccine treatment. Among Patients that received Ipilimumab and standard therapy, ~ 21% were still alive after three years while it was 12% for patients that received standard therapy. Good data obtained in Ipilimumab clinical trials subsequently led to its approval by FDA to treat metastatic melanoma patients for whom the first line of therapies have failed. Dr. Veerendra Koppolu, Scientist from AstraZeneca, USA has thoroughly presented the clinical development of Ipilimumab in his recent articles.
Nivolumab is an antibody that targets an inhibitory receptor Programmed Death-1 (PD-1) that is expressed on the surface of T cells. PD-1 interacts with ligands PDL-1 and occasionally with PDL-2 that are expressed on surface of antigen presenting cells or other immune cells or tumor itself. The PD-1/PDL-1 ( or PDL-2) Interactions render T cell inactive and prevents further proliferation and cytokine production. So targeting these interactions using nivolumab blocks the PD-1 and PD L-1 negative regulation pathway.
Nivolumab is found to be effective against advanced melanoma and showed 72.9% Survival rate after 1 year and 22% after 3 years in Phase III trial. Nivolumab is approved by FDA in 2015 for treating metastatic melanoma. Subsequent clinical trials also suggest the effectiveness of nivolumab against renal carcinoma and non-small cell lung cancer. Among several forms of immunotherapy, nivolumab appears to have high response rate. This may be because of wide distribution of PD-1 in various tissues (lymphoid, myeloid, dendritic, microvascular endothelial cells) and organs (heart, lung, pancreas, muscle and placenta) suggesting that interactions of PD-1 with its ligand may be important in regulating T cells in peripheral tissues and inhibition of these with nivolumab may trigger a broader activation of T cells responses.
Pembrolizumab and Durvalumab
Both Pembrolizumab and Durvalumab target PD-1/PDL-1 interactions through directly binding to PDL-1 and inhibiting its interaction with PD-1. Pembrolizumab is approved in 2015 and is now used to treat multiple cancers such as advanced non-small cell lung cancer, advanced melanoma, head and neck squamous cell cancer, classical Hodgkin lymphoma, and advanced urothelial bladder cancer. Durvalumab is approved in 2017 by FDA for patients suffering from late stage urinary bladder cancer.
Adaptive T cell therapy
Steven Rosenberg from National Institute of Health (NIH) in USA have developed chimeric antigen receptor (CAR) T cell based adaptive immunotherapy technology which involves genetic engineering of patient T cells to target tumor cell. In CAR-T therapy, patient’s T cells are engineered in such a way that they will provide T cell with exquisite tumor antigen specific recognition, T cell activation, and proliferation.
The major advantage of CAR T cell therapy is that it is not affected by mechanisms that are developed by tumor cells to evade immune responses. It is independent of MHC dependent antigen presentation which generally limits endogenous T cell response when tumors downregulate MHC expression on their surface. CARs can detect a variety of antigens expressed on tumor cell surface including proteins, lipids, carbohydrates for which antibodies can be generated. CAR therapy can overcome the limitations of poor endogenous T cell immune response that are the result of cancer cell induced down regulation of the co-stimulatory molecules.
Although CAR T cell therapy is relatively a new immunotherapy approach, the clinical results are eye-catching. Clinical studies reported that 27 (90%) out of 30 acute lymphoblastic leukemia (ALL) patients that have undergone CAR T cell therapy targeting CD19 (CTL019) responded with a complete remission. A high response was achieved even for patients with previously failed stem-cell transplantation (15 out of 30). This unprecedented early success of CAR T cell therapy raised enormous interest and now became the focus of many clinical trials. This first CAR-T cell therapy against acute lymphoblastic leukemia is under FDA review and the recent FDA advisory committee meeting unanimously (10:0) recommended the approval of this therapy.