When cancer begins to develop within the body, the immune system has its own inherent response to the newly uncontrolled cell growth. This response is highly dependent on a coordinated system of checkpoints within the immune system’s cells. Unfortunately, cancer cells rapidly mutate and produce ligands that aim to confuse the immune system resulting in decreased detection and destruction. Immunotherapy looks to bolster the body’s own immune response to cancer, and help it adapt more effectively to the evasion techniques utilized by tumors. Much of previous immunotherapy research had included less specific monoclonal antibodies (mAbs) and cancer vaccines; however, a new wave of clinical trials have re-focused on more specific signals and checkpoints within the cell cycle.
The recent ASCO 2012 meeting provided exciting new data from a wide array of chemotherapeutic modalities. Some of the most impressive data was in the area of immunotherapy, in which several abstracts reported positive Phase 1 results in antibodies targeting the programmed death (PD-1) receptor, and one of its ligands, PD-L1, which represent key checkpoints within the immune system. The biochemistry behind cancer is complicated in itself; however, the unique pathways that these checkpoint compounds target could help illuminate new ways to put cancer cells in check.
PD-1, a transmembrane protein receptor that can be found on activated T-cells, binds to two different ligands, PD-L1 and PD-L2. Interaction of PD-1 and PD-L1 causes an overall inhibitory effect on the body’s immune response to cancer by reducing the activity of circulating B-cells and T-cells. Cancer cells use this interaction as a way to evade the immune system, and continue to grow. In preclinical and in vitro studies, PD-L1 has been shown to be expressed on cells directly transformed by the tumor, and a more specific marker in tumor cells than CTLA-4 ligands previously tested. This could offer an improved attack on cancer cells compared with the older, broader-acting compounds that work through CTLA-4. PD-1 knockout mice (removed from their genetics) showed an increased propensity for autoimmune diseases, which further supports the notion that inhibition of the PD-1/PD-L1 interaction leads to increased activity of the immune system. The most recent Phase 1 data from the anti-PD-1 antibody showed a complete or partial response rate between 18% and 28% in NSCLC, RCC and melanoma with a grade 3 or 4 toxicity rate of 14%. Similarly, recent Phase 1 data from the anti-PD-L1 antibody reported between a 6% and 17% complete or partial response rate in the same aforementioned solid tumors with a grade 3 or 4 toxicity rate of 9%.
Aside from PD-1 and PD-L1, there are also several other immune checkpoint modulators being studied. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors act by preventing the degradation of tryptophan in hopes of reversing the immunosuppression caused by tryptophan’s metabolites within immune-system cells. Memory B-cells and their anti-MICA antibodies are being collected from patients who had previously responded to immunotherapy in hopes of honing in on the benefits of maintaining natural killer cell activity against tumors. Although this technique appears similar to previous attempts at cancer vaccine development, it could also be used in developing new, more targeted mAbs.
Tumor resistance will undoubtedly continue to present a major challenge in the development of effective chemotherapeutic agents. It is clear that immune-system checkpoints such as PD-1 and PD-L1 will play a critical role in combating this resistance. Although early-phase data appears promising for these compounds, it will continue to take innovative efforts at elucidating the intricacies within the immune system’s own checkpoint system to strike the correct balance between efficacy and patient safety.
- What role do you think immunotherapy will play in the future of chemotherapy?
- Do you think that there are any additional roadblocks to immunotherapy becoming a mainstay in chemotherapeutic regimens?
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