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In 2018, the Nobel Prize in Physiology or Medicine was awarded to the inventors of immune checkpoint blockade therapy, a “game-changing” technology that initiated a paradigm shift in cancer management. Checkpoint blockade therapy works by unleashing the immune surveillance against cancer by blocking the “natural brakes” (checkpoints) in the immune system, which are exploited by tumors as an immune-evasive strategy. Despite there being a substantial increase in the FDA approval rate for new antibody therapeutics targeting immune checkpoints, patient response to these treatments is typically modest. Rothschilds et al. have pinned down the reason for this limited success to the lack of efforts directed towards understanding the importance of ‘when’ in immunotherapy.
Immune response to an infection is a well-coordinated set of events that begins when an immune cell encounters a foreign agent, which culminates in the elimination of the foreign invasion. However, effective immune activation is thwarted by pathophysiological processes of free-wheeling cancer cells, resulting in an immunocompromised state. To remedy the lack of immune surveillance, immunotherapy utilizes protein antigens, small molecule drugs, and in some cases, even cells to sensitize immune cells to the prevailing disease. Rothschilds and Wittrup explain that the administration of immunotherapy commences a cyclical wave of immune defenses that proceed through the following milestones: (1) The tumor antigen is taken up by a specialized class of immune cells called antigen-presenting cells (APCs), (2) APCs sample the antigen and present it to T cells, and (3) primed T cells, which can be thought of as trained anti-cancer warriors, traffic to the tumor site and engage in direct combat. The delay between each of these milestones can be between hours to days, and therefore, per the authors suggestion, an optimal dosing schedule would be one that is in sync with the immunological clock.
These investigators further elaborate that, contrary to conventional understanding, prolonged administration of treatment does not necessarily translate to improved efficacy. A classic example of this is the CheckMate 067 clinical trial. The purpose of the trial was to study treatment outcomes in patients that received a combination of two checkpoint inhibitors versus any single one. An intriguing finding of the study was that patients who completed the treatment presented outcomes that were comparable to ones that discontinued, questioning the rationale for a longer treatment duration when a shorter treatment duration could produce the same result.
Since immune checkpoint inhibitors are used to reinforce the immune system, their combination with any other kind of therapy can benefit from optimal temporal dosing strategies. A study investigating the combination of anti-CTLA-4, an immune checkpoint inhibitor, and radiation therapy (RT) for treating a mouse model of colon cancer found that using a dosing sequence of anti-CTLA followed by RT was more effective than administering them together. Radiation therapy is a therapeutic intervention used for destroying cancers that are locally contained by exposing them to high-energy ionizing radiation. On the other hand, anti-CTLA-4 boosts immune activation by countering immune-suppression by tumors by inhibiting regulatory T cells (Tregs), which are negative regulators of T-cell activation. As the role of anti-CTLA-4 is further down in the immune response, it’s only fitting that the tumors are first exposed to RT to initiate tumor cell death, which will, in turn, generate tumor antigens needed to activate T cells followed by anti-CTLA-4 counterattacking of immune-suppression.
A poorly timed dosing interval disrupts the natural rhythm of immunity and can snowball into adverse effects, resulting in treatment failure. Careful consideration of ‘when’ can help rescue therapeutic combinations that have been shelved due to the lack of synergy. Striking a balance between safety and efficacy is key to the success of immuno-oncology. The addition of an extra dimension of time in immunotherapy, along with other considerations, could unlock the full potential of immunotherapy that has gone largely untapped.
Edited by Emily Bonacquisti
Rothschilds, A. M., & Wittrup, K. D. (2019). What, Why, Where, and When: Bringing Timing to Immuno-Oncology. Trends Immunol, 40(1), 12-21. doi: 10.1016/j.it.2018.11.003
Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J. J., Cowey, C. L., . . . Larkin, J. (2017). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New England Journal of Medicine, 377(14), 1345-1356. doi: 10.1056/Nejmoa1709684
Young, K. H., Baird, J. R., Savage, T., Cottam, B., Friedman, D., Bambina, S., . . . Crittenden, M. R. (2016). Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy. PLoS One, 11(6).
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