Immune Checkpoint Inhibitors
Immune checkpoint inhibitors are a type of immunotherapy drug that helps boost the body's natural defenses to fight cancer. These Immuno-oncology Drugs target molecules called checkpoints that are present on immune cells and cancer cells. Checkpoints act as brakes that keep immune responses from becoming too strong. Some cancers use these checkpoints to avoid detection and evade immune responses. Immune checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 drugs function by releasing these brakes and allowing T cells to mount an anti-tumor response.
PD-1 inhibitors were the first immune checkpoint drugs approved by regulatory agencies and include drugs like pembrolizumab and nivolumab. PD-1 is found on T cells and when it binds to PD-L1 on tumor cells, it turns off the T cell response. PD-1 inhibitors block this interaction, which reactivates the T cells to attack cancer cells. Clinical trials have shown significant overall survival benefits in advanced melanoma and lung cancer patients treated with PD-1 inhibitors compared to standard chemotherapy. They are now approved for several cancer types like lung cancer, melanoma, Hodgkin's lymphoma and kidney cancer.
CTLA-4 inhibitors were the first immune checkpoint drugs developed and ipilimumab was the first to gain approval in 2011. CTLA-4 acts earlier in the immune response than PD-1 and competes with CD28 to bind to B7 molecules on antigen-presenting cells. Blocking CTLA-4 helps enhance T cell activity and proliferation. Ipilimumab has shown improved survival outcomes and is approved for the treatment of metastatic melanoma.
These checkpoint inhibitors have durably improved survival for many cancer patients who had limited treatment options in the past. However, only a proportion of patients respond to these drugs due to tumor resistance mechanisms. Combining checkpoint inhibitors with other immuno-oncology drugs or conventional therapies may help increase response rates.
Cancer Vaccines
Cancer vaccines aim to boost anti-tumor responses by eliciting protective T cell immunity. They can be designed to target specific tumor antigens that are highly expressed on cancer cells. Sipuleucel-T was the first therapeutic cancer vaccine approved by the FDA in 2010 for prostate cancer. It involves collecting antigen-presenting cells from the patient, activating them ex vivo with a prostate cancer antigen, and reinfusing them to stimulate T cell responses. Sipuleucel-T improved median survival by 4 months compared to placebo in metastatic castration-resistant prostate cancer.
Other cancer vaccine approaches involve direct administration of DNA or RNA encoding tumor-associated antigens. mRNA-based personalized neoantigen vaccines have shown promise in early trials and aim to induce T cell responses against patient-specific mutations. A personalized neoantigen vaccine encoding seven mutations was able to shrink tumors completely or partially in 9 out of 18 melanoma patients. Viruses engineered to deliver cancer antigens can also be used as therapeutic cancer vaccines. Oncolytic viruses can selectively replicate in tumor cells and induce immunogenic cell death, leading to antigen release and uptake by dendritic cells. Immuno-oncology drugs viruses are currently being investigated alone or in combination with other therapies.
Adoptive Cell Therapy
Adoptive cell therapy involves extracting lymphocytes like T cells from patients or donors, activating and manipulating them outside the body, and reinfusing the cells in large numbers to seek out and destroy cancer cells. One form of this therapy called chimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical responses in certain blood cancers. CAR T cells are engineered to express chimeric antigen receptors that can recognize specific tumor antigens independently of human leukocyte antigen presentation.
Anti-CD19 CAR T cells targeting the B cell antigen CD19 have led to complete remission rates over 80% in relapsed/refractory B cell acute lymphoblastic leukemia and mantle cell lymphoma. The first two CD19 CAR T cell products, tisagenlecleucel and axicabtagene ciloleucel, were approved by the FDA in 2017 based on clinical trials showing durable responses lasting years. However, CAR T cell therapy is also associated with severe side effects like cytokine release syndrome and neurotoxicity that require careful patient selection and monitoring. Ongoing research focuses on making CAR T cells safer and applicable to more solid tumors. Other types of adoptive cell transfer under investigation include tumor-infiltrating lymphocytes and T cell receptors targeting neoantigens.
Combination Immunotherapy
Harnessing synergy between different immunotherapeutic approaches may help overcome primary and acquired resistance to single agents. Combining immune checkpoint inhibitors with other agents that stimulate anti-tumor immunity through distinct mechanisms could achieve higher response rates than monotherapies. Some immunotherapies being combined in clinical trials include immune checkpoint inhibitors with cancer vaccines, oncolytic viruses, chemotherapy or targeted therapies.
Initial results from these combination studies have been promising. For example, the Phase III CheckMate -227 trial showed that adding nivolumab to chemotherapy significantly prolonged survival in non-small cell lung cancer compared to chemo alone. Combining ipilimumab and nivolumab also led to higher response rates than either drug alone in multiple tumor types according to CheckMate -067. Results fromCheckMate -9LA confirmed that 3-year overall survival with the dual immunotherapy combination was significantly improved compared to standard of care in stage 3 lung cancer. Ongoing trials continue exploring new immunotherapeutic combinations to make checkpoint inhibition more effective or broaden eligibility across cancer types.
The Future of Immuno-oncology
Immuno-oncology drugs has transformed the treatment landscape for many cancers within a short period of time. Further exploration is still needed to fully realize the potential of immunotherapy and overcome challenges around primary and acquired resistance. Areas of active research include combinations with targeted therapies that modulate tumor microenvironment; bispecific antibodies that bridge innate and adaptive immunity; checkpoint inhibitors targeting new targets like TIGIT, LAG3 and TIM3; personalized neoantigen vaccines; CAR technologies targeting solid tumors; and combination adoptive cell therapy approaches. Immuno-oncology is a thriving field with more discoveries expected to expand the armamentarium of effective and durable treatments available to cancer patients in the years.
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