Cherry Chau

Introduction. Cancer immunotherapy has sometimes been referred to as the “holy grail of oncology” because it activates the patient’s own immune system to kill cancer cells. PD-1 and CTLA-4 have long been identified as potential targets for immunotherapy.¹ They are receptors that downregulate T-cell activity to “turn off” the immune system after an infection has been resolved. Specifically, PD-1 inhibits T-cell proliferation by blocking progression through the cell cycle,^2,3 while CTLA-4 is expressed on regulatory T-cells to inhibit T-cell activation.⁴ Multiple cancers have been shown to upregulate PD-L1 and CTLA-4 to their own advantage to escape immune surveillance.^5-6 Blocking these immunosuppressive molecules via anti-PD-1 and anti-CTLA-4 antibodies have been found to have both distinct and synergistic immunological effects that have potential to activate the immune system against cancer cells.⁷  Methods. The main study examined 3 groups of patients: those receiving anti-PD1 antibodies, anti-CTLA-4 antibodies, or both.⁷ Patient T-cells were analyzed both before and 3 weeks after therapy for changes in gene expression profiles. Results. T-cells showed distinct patterns of changes in gene expression that were largely unique to each therapy.⁷ Combination therapy led to more changes in more genes than either single therapy alone. Over 400 genes were affected with combination therapy compared to only 36 with anti-PD-1 and 26 with anti-CTLA-4. PD-1 blockade preferentially activated genes involved in T-cell cytolytic function (such as granzyme genes) as well as T-cell regulation. CTLA-4 blockade and combination blockade preferentially activated genes involved in T-cell proliferation, most notably Ki-67. These changes in immune cells understandably led to differences in circulating plasma cytokine levels. CXCL10 levels were increased with all three therapies, but IL-2R and IL-8 levels were increased only with combination therapy. IL-1a increased with anti-PD-1 therapy and combination therapy, but not anti-CTLA-4 therapy.⁷  Conclusions. This comparison indicates that each treatment imprints its own “signature” onto circulating immune cells. It also suggests that combination therapy may have synergistic effects that cannot be elicited with either therapy alone, which may influence which treatment a patient should receive. Despite these optimistic discoveries, it has been shown that some cancers can overcome PD-1 and CTLA-4 blockade by manipulating other components of the immune system, such as the tumor suppressor PTEN.⁸ This emphasizes the importance for future research to explore different combinations of immunotherapies that are not necessarily limited to targeting PD-1 and CTLA-4.

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