Advancements of Common Gamma-Chain Family Cytokines in Cancer Immunotherapy

Abstract

The approval of immunotherapies such as checkpoint inhibitors (CPIs), adoptive cell therapies and cancer vaccines has revolutionized the way cancer treatment is approached. While immunotherapies have improved clinical outcome in a variety of tumor types, some cancers have proven harder to combat using single agents, underscoring the need for multi-targeted immunotherapy approaches. Efficacy of CPIs and cancer vaccines requires patients to have a competent immune system with adequate cell numbers while the efficacy of adoptive cellular therapy is limited by the expansion and persistence of cells after infusion. A promising strategy to overcome these challenges is combination treatment with common gamma-chain cytokines. Gamma-chain cytokines play a critical role in the survival, proliferation, differentiation and function of multiple immune cell types, including CD8 T-cells and NK cells, which are at the center of the anti-tumor response. While the short half-life of recombinant cytokines initially limited their application in the clinic, advancements in protein engineering have led to the development of several next-generation drug candidates with dramatically increased half-life and bioactivity. When combining these cytokines with other immunotherapies, strong evidence of synergy has been observed in preclinical and clinical cancer settings. This promising data has led to the initiation of 70 ongoing clinical trials including IL-2, IL-7, IL-15 and IL-21. This review summarizes the recent advancements of common gamma-chain cytokines and their potential as a cancer immunotherapy.

Engineered red blood cells (activating antigen carriers) drive potent T cell responses and tumor regression in mice

“…Given the apparent role of DCs in driving responses, immune stimulators that augment priming, such as anti-CD40 or anti-CTLA4 could be explored (3,67,(74)(75)(76)(77). During expansion of antigen-specific CD8 + T cells, delivery of cytokines may augment proliferation of CD8 + T cells and enhance their activity (78). Once in the tumor, therapeutic agents that modulate the tumor microenvironment such as anti-PD1, anti-PD-L1, anti-TGFb, anti-TIM-3, and others could be viable options (77,79,80).…”

The application of Interleukin-2 family cytokines in tumor immunotherapy research

“…In summary, we have made a brief overview of some representative engineered IL-2 cytokines that are expected to be candidates for the next generation of immunotherapies. In reality, there are also an increasing number of experiments focusing on IL-2 cytokine in combination with adaptive cell transfer (ACT), cancer vaccines (49), chemotherapeutic drugs and surgical operation. Those studies will not be covered in detail in this review.…”

Use of CD122+ natural killer cell precursors for superior anti-leukemia responses

“…Consequently, low levels of IL-2 are likely to induce an anti-inflammatory response by expanding Tregs, while an immunostimulatory effect requires high-dose (HD) IL-2 and is associated with serious toxicities 35,36 . Next-generation IL-2 molecules for cancer therapy are being developed to harness the immunostimulatory effect of IL-2 while avoiding Treg stimulation and toxicity 37,38 .…”

“…IL-2 was the first common gamma-chain family cytokine to be discovered as a T-cell growth factor and later understood to function as an inducer of requires high-dose (HD) IL-2 and is associated with serious toxicities 35,36 . Nextgeneration IL-2 molecules for cancer therapy are being developed to harness the immunostimulatory effect of IL-2 while avoiding Treg stimulation and toxicity 37,38 .…”