While immunotherapies have made great strides in the fight against cancer, it is not a one-size-fits-all situation. Different types of immunotherapy have distinct side effects, and some are more effective for certain cancers than others. In addition, a patient’s overall health, strength of their immune system, and the type of cancer all play a role in which immunotherapy is available and will have the greatest chance of being effective.
After considering all relevant factors, including potential autoimmune toxicity, it may be determined a single or combination therapy regimen, including all standard and novel cancer therapies (chemotherapy, radiation, molecularly targeted therapies), is warranted to improve the likelihood of successful treatment. The potential synergy provided by combination therapies could make the tumor more immunogenic, thus enhancing the effectiveness of immunotherapy.
Radiation therapy has been shown to stimulate immune mediators thereby enhancing anti-tumor immune response. Combining radiation with immunotherapy could enhance the efficacy seen with single agent immunotherapy treatments. Combination therapies may allow for more personalized cancer treatment in order to provide the maximum potential benefits of each therapeutic agent.
Advances in immunotherapy treatments are aimed at the potential for initiating a self-sustaining immune response against cancer cells resulting in long-term clinical benefits and reduced incidence of recurrence. While single immunotherapy treatment regimens have shown increasing response rates and durability across all cancer types, a high percentage of patients still fail to respond and the potential for tumors to become resistant over time to these agents still exists.
Therefore, research has turned its focus to the potential of combining immunotherapies with current clinical therapies in addition to other immunotherapy agents in hopes of improving response rate and long-term outcomes for patients. However, combination therapies have their own clinical and economic considerations that must not be overlooked.
Enhancing the immune response has the potential to send the immune system into overdrive thus resulting in serious and sometimes critical autoimmune reactions that can be further exacerbated by the combination with another therapy with similar effects on the immune response. Additionally, single agent immunotherapy alone is expensive, thus using another therapeutic agent increases this already elevated cost.
Future studies need to consider these challenges and potential alterations in the dose of therapies when combined with other therapeutic agents, sequence of therapies, selection of a meaningful endpoints, and selection of appropriate patient populations.
While immune checkpoints are used to prevent T cells from turning against normal cells, tumors have found ways to exploit these pathways complicating the potential therapeutic mechanisms. Nonetheless, currently, combination immunotherapy regimens are often targeted at immune checkpoint inhibitors, PD1/PD-L1 axis and cytotoxic T-lymphocyte antigen 4 (CTLA-4). The combination of PD-1 and CTLA-4 inhibitors are currently being assessed in clinical trials for multiple malignancies, including stomach, breast, bladder, pancreatic, renal, lung and ovarian cancers. In addition, phase 1 and 2 studies are underway combining PD-1 with radiation therapy with promising preliminary results.
Example of FDA Approved Therapy
Pembrolizumab is often used in combination therapy regimes. There are over 1,700 clinical trials investigating pembrolizumab in combination with other cancer therapies. Currently, pembrolizumab is approved in combination with chemotherapy, carboplatin and paclitaxel, as a first line treatment of patients with metastatic squamous non-small cell lung cancer and has shown longer overall and progression free survival in patients then chemotherapy alone.
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