Immunotherapy: Why the hype?Over the last few years immunotherapy has become one of the hottest topics in oncology. The role of the immune system in protecting against cancer has been known about for decades but only recently have effective regimes been achieved. Most notably, mono-clonal antibody blocking of CTLA-4 and PD1 have shown most promise, leading to long term survival in subsets of patients. However immunotherapeutic strategies also include vaccines, viruses, adoptive transfer of T and NK cells and other antibodies and recombinant proteins.
Whats the theory? |
A simple overview of the science
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The genetic and epigenetic changes of a cancerous cell produce antigens that the immune system recognize as foreign (neo-antigens) and therefore target for destruction. This applies a strong selection bias on cancer cells to develop resistance mechanisms to evade this immune response, including activating immune checkpoints on T cells that downregulate immune responses. It is possible to fight back by either stimulating increased immune surveillance or to inhibit the cancers evasion mechanisms. Vaccination with tumour antigens or administration of activated T cells as part of adoptive cellular therapy aim to achieve the former, increasing the activity of the immune system. The use of antibodies against immune-checkpoint molecules such as CTLA-4 and PD1 are examples of interrupting cancers immune system evasion mechanisms.
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A Nature film focusing on immunotherapy in melanoma
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A Nature film giving a more in-depth discussion on the various types of immunotherapy
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Immune Checkpoint Inhibitors: CTLA-4 and PD-1
Immune checkpoint inhibitors are the type of immunotherapy that has had the most success trials and greatest impact on current practice.
Cancer cells can develop mechanisms that exploit immune system ‘off switches’ or checkpoints that have evolved to stop overwhelming immune responses. CTLA-4 is such an inhibitory receptor which functions to down-regulate initial T cell activation. This led to the design, clinical trains and subsequent approval of ipilimumab by the FDA in 2011 by the FDA and 2012 in Europe as first-line therapy for patients with metastatic melanoma. Data showed that a small subset of patients could achieve long-lasting survival at a previously terminal stage of disease. Disadvantages include a slow rate of response as the effect may take months to appear so it difficult to quickly know which patients will respond as well as significant immune-related toxicities. As research has progressed in metastatic melanoma, ipilimumab it is now licensed for combination with nivolumab a PD-1 monoclonal antibody.
The PD-1 inhibitor is another receptor expressed by antigen-stimulated T cells that inhibits T cell proliferation, cytokine release and cytotoxicity. The two best known anti-PD-1 antibodies are pembrolizumab and nivolumab. The former has been licensed for melanoma and non-small cell lung cancer whilst nivolumab is licensed for both and also renal cell carcinoma.
Many clinical trials are now testing these agents in combinations in many different tumour settings. As combining most drugs, this typically increases the rate of side effects and toxicities. Most side effects of immunotherapy, as it involves over activation of the immune systems responds well to immunosuppression with steroids. However, data on long term safety is pending.
The interaction between conventional cytotoxic chemotherapy and immunotherapy is of interest. Obviously, many chemotherapy agents suppress the immune system (e.g. neutropenic sepsis) yet they may also assist, for instance by releasing many new antigens when cancer cells are destroyed. Other interesting avenues are trying to improve the tumour microenvironment for immune cells for example by inhibiting vascular endothelial growth factor signaling that promotes angiogenesis in cancers.
It is clear that immunotherapy can lead to astounding responses in a small subset of patients. Significant research is taking place into how to predict this subset of patients using biomarkers so as to avoid the cost and side effects of treating a patient who will not respond.
Cancer cells can develop mechanisms that exploit immune system ‘off switches’ or checkpoints that have evolved to stop overwhelming immune responses. CTLA-4 is such an inhibitory receptor which functions to down-regulate initial T cell activation. This led to the design, clinical trains and subsequent approval of ipilimumab by the FDA in 2011 by the FDA and 2012 in Europe as first-line therapy for patients with metastatic melanoma. Data showed that a small subset of patients could achieve long-lasting survival at a previously terminal stage of disease. Disadvantages include a slow rate of response as the effect may take months to appear so it difficult to quickly know which patients will respond as well as significant immune-related toxicities. As research has progressed in metastatic melanoma, ipilimumab it is now licensed for combination with nivolumab a PD-1 monoclonal antibody.
The PD-1 inhibitor is another receptor expressed by antigen-stimulated T cells that inhibits T cell proliferation, cytokine release and cytotoxicity. The two best known anti-PD-1 antibodies are pembrolizumab and nivolumab. The former has been licensed for melanoma and non-small cell lung cancer whilst nivolumab is licensed for both and also renal cell carcinoma.
Many clinical trials are now testing these agents in combinations in many different tumour settings. As combining most drugs, this typically increases the rate of side effects and toxicities. Most side effects of immunotherapy, as it involves over activation of the immune systems responds well to immunosuppression with steroids. However, data on long term safety is pending.
The interaction between conventional cytotoxic chemotherapy and immunotherapy is of interest. Obviously, many chemotherapy agents suppress the immune system (e.g. neutropenic sepsis) yet they may also assist, for instance by releasing many new antigens when cancer cells are destroyed. Other interesting avenues are trying to improve the tumour microenvironment for immune cells for example by inhibiting vascular endothelial growth factor signaling that promotes angiogenesis in cancers.
It is clear that immunotherapy can lead to astounding responses in a small subset of patients. Significant research is taking place into how to predict this subset of patients using biomarkers so as to avoid the cost and side effects of treating a patient who will not respond.
Image of a group of killer T cells (green and red) surrounding a cancer cell (blue, center). The killer cell then uses special chemicals housed in vesicles (red) to destroy the cancer cell. Image from NIH, U.S.A. Image in Public Domain.