Optimising the use of immunotherapies to treat cancer 

Cancer cells

Sharad Adekar, Medical Chair Lead and Currien MacDonald, Medical Chair Director at WCG, discuss the risks and benefits of using immunotherapies to treat cancer. 

In the last decade, a paradigm shift has occurred in the landscape of cancer treatment1. Supported by current advances in understanding of the mechanism and pathways regulating immune system activation and suppression, cancer cells evading the immune system, and the cancerous tumour microenvironment, immunotherapy can now harness the power of a person’s immune system to fight cancer2. There are multiple modalities of immunotherapeutic agents that utilise this power to identify, treat, control, and prevent cancer. The types of immunotherapies include, but are not limited to, immune checkpoint inhibitors, adoptive cell therapies, cytokines, oncolytic viruses, and cancer vaccines. Although immunotherapy has been successful in transforming cancer treatment, each of these powerful agents has specific issues to consider when using them. These include direct side effects, autoimmunity, off-target effects, and associated treatment burden and expense (see Table 1). 

Direct side effects 

Some immunotherapies have substantial direct side effects; that is, their mechanism of action produces unwanted but unavoidable reactions. For example, cytokines are powerful stimulants of the immune system, but they also cause fever, chills, fatigue, and stomach side effects. Cell-based therapies can produce cytokine release syndromes as they activate, with very serious side effects that can progress. Checkpoint inhibitors can have immediate reactions, and oncolytic viruses also can trigger cytokine and cell lytic side effects.  

Autoimmunity 

Stimulating the immune system to attack cancer cells may over stimulate it, leading to it reacting to normal tissue. Checkpoint inhibitors are associated with immune-related adverse events, which may be severe or fatal, can occur in any organ system, and can affect more than one body system simultaneously. Similarly, immune checkpoint inhibitors are associated with risks of allograft rejection, a major concern for their use in solid organ transplantations3. Autoimmune activation can also occur with cancer vaccines, whereby they are directed at normal tissue as well as the cancer. 

Off-target effects 

Immunotherapies’ ability to target a cancer specifically is not new to oncology treatment. Monoclonal antibodies or CAR-T cells can be made with high specificity that allow cancer cells with a difference from their normal cell types to be targeted by the immune system. At the same time, if the immunotherapy targets another, healthy tissue, serious side effects can result. Other potential risks from CAR-T include neurotoxicity or the cells becoming cancerous.   

Treatment burden and expense 

The ability to use a person’s own immune cells or to create a vaccine from their own tumour to treat their cancer brings a chance for powerful and lasting effects. However, the effort and expense in manufacturing a drug for one person puts an immense burden on that person and the health care system. Making these individualised treatments can also impact the person as they wait for treatment to start while their illness potentially progresses. Cell-based treatments can also use a drug regimen to suppress the recipient’s immune system to promote successful adoption of the treatment. This leaves the person at risk of infections and the direct side effects of the drugs, such as nausea and fatigue.  

Solutions to deal with immunotherapy issues 

To maximise the risk/benefit of immunotherapies requires managing their unique adverse events. Prevention, early detection, and prompt treatment of immune-related adverse events can limit short- and long-term damage. Methods include: 

  • Prophylactic or premedication to limit autoimmune and off-target events 
  • Close monitoring for symptoms and signs of autoimmune reactions 
  • Use of multi-team specialty consultation for early diagnosis and treatment of direct effects and off-target effects 
  • Appropriate supportive and toxicity specific management guidelines, such as prescribing tocilizumab or equivalent for cytokine release syndrome  
  • Prompt decisions to withhold or discontinue the agent if autoimmune reactions occur 
  • Advances in cell-therapy and vaccine technology to allow off-the-shelf treatment 

Role of sponsors, investigators, and regulatory authorities 

In the larger scope, the unique adverse events of immunotherapies need to first be addressed in the clinical trials that test them. Sponsors and investigators involved in developing study designs can create distinct protocol designs that take into account these issues. For example, blinding and placebo controls may not be feasible or may place unreasonable risks on participants. 

With innovative treatments comes a need for innovative approaches to manage adverse events and ensure patient safety. The identification, development and use of specific, novel biomarkers which can predict early signals of toxicity and allow use of effective countermeasures in a timely manner could play a significant role. Improved preclinical models, including virtual models, for detection, treatment, and prevention of adverse effects prior to immunotherapy testing in humans are needed. Accurate predictive tools for use prior to and during investigations can help determine people who would benefit from or be intolerant of immunotherapies more effectively.  

Several examples include: 

  • Immune checkpoint inhibitors: identification of new targets for immune checkpoints and clinical studies  
  • Adoptive cell therapies: development of new generation CAR-T cells, gene editing technologies, use of neo-antigens, and the identification of new targets may improve the functionality, efficacy and reduce toxicities associated with cell therapies 
  • Oncolytic viruses and vaccines: new delivery systems can help in preventing direct and off-target side effects 

Standard measures in clinical trials require specific knowledge of these issues to be most effective. The inclusion and exclusion of appropriate participants in immunotherapy clinical trials will increase the investigational product’s efficacy and reduce unnecessary toxicities. The safety and efficacy evaluation and study end points will also require attention to the immunotherapy-specific issues.  

As these are not just standard oncology treatments, the investigators and staff at the clinical sites need sufficient and specific training and additional supplies to deal with immunotherapy issues. Examples include the availability of a multi-specialty team or known specialised consultants and resources to prevent and manage toxicities that can arise with multiple organ systems. The staff can also play an important role in educating study participants and their families about the signs and symptoms of possible adverse events associated with immunotherapies, and what measures to take or whom to call in case of an occurrence. 

As immediate side effects are not the only toxicity issue with these therapies, the treatment burdens and expenses laid upon patients or participants in research need a solution at a higher level. Regulatory authorities, including the Institutional Review Board (IRB), can also play an important role in assessing clinical trials to ensure an equitable selection of participants. They need to not only consider physical risk minimisation but also look to support reimbursement and integrate community support into trials. Concerns about the cost of immunotherapy, especially cell-based therapies like CAR-T, need attention from country regulators and health care systems in the context of long-term impacts to people. Expensive immunotherapy can create a financial burden both on patients and the health care system. Treatments that produce remission, but that patients and society cannot afford, are not very effective. 

Conclusion 

Immunotherapy can harness the power of the immune system in fighting cancer. Immunotherapies such as immune checkpoint inhibitors and adoptive cell therapies like CAR-T cells have revolutionised the landscape of cancer treatment. But these immunotherapies can also be associated with life threatening immune-related adverse events involving multiple organ systems simultaneously, cytokine release syndrome, and neurotoxicity.  

We need more research to identify specific biomarkers that can assist in early detection, prevention and management of adverse events, and better strategies to deal with them. The sponsors and investigators conducting immunotherapy research and the regulatory authorities reviewing it need to be aware of the issues and ensure there is proper monitoring, supportive therapies, staff training and other required resources at each site to safely manage this new class of treatment. Based on more extensive research, study designs, new generation technologies will provide us with the ability to understand, prevent and treat these adverse effects. 

About the authors 

Sharad Adekar, MD, PhD, CIP, is a Lead Medical Chair at WCG’s IRB in Puyallup, Washington. He is a physician scientist with clinical experience in family practice and paediatrics and research experience in immunology, oncology, cardiovascular diseases, infectious diseases, and neurology. Dr. Adekar has experience in human antibodies in terms of discovery, lead optimisation, and preclinical development of monoclonal antibody therapeutics.  

Currien MacDonald, MD, CIP, is Medical Chair Director at WCG and contributes to biosafety reviews for WCG’s institutional biosafety committee. Dr. MacDonald was previously Medical Director for Aspire IRB, and Vice Chair of Canadian REB. After graduating from the University of Minnesota Medical School, Dr. MacDonald completed a family medicine residency program as Chief Resident. He delivered primary care for five years in San Diego, CA. and served as a medical consultant to the University of California, San Diego.  

 References 

  1. McCune JS. Rapid advances in immunotherapy to treat cancer. Clin Pharmacol Ther 2018;103:540‑4.
  2. Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015;35 (Suppl):S185‑98.
  3. Haanen J, Ernstoff M, Wang Y, et al. Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy. Ann Oncol 2020;31:724-44 

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