Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

Abstract

T cell engaging therapies, like CAR-T cells and T cell engagers, redirect T cells toward tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing. T cell receptor or CAR-T downstream signaling triggers a release of pro-inflammatory cytokines, which can induce a Cytokine Release Syndrome (CRS). The incidence of CRS is still hardly predictable among individuals and remains one of the major dose-limiting safety liabilities associated with on-target activity of T cell engaging therapies. This emphasizes the need to elaborate mitigation strategies, which reduce cytokine release while retaining efficacy. Here, we review pre-clinical and clinical approaches applied for the management of CRS symptoms in the context of T cell engaging therapies, highlighting the use of tyrosine kinase inhibitors as an emerging mitigation strategy. In particular, we focus on the effects of Bruton’s tyrosine kinase (BTK), Src family including Lck, mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK) inhibitors on T cell functionality and cytokine release, to provide a rationale for their use as mitigation strategies against CRS in the context of T cell engaging therapies.

Mechanistically modeling peripheral cytokine dynamics following bispecific dosing in solid tumors

“…A key finding here is that peripheral cytokine dynamics following bispecific dosing is dominated by cytokine production in healthy tissue. This finding is consistent with current scientific understanding: on‐target off‐tumor effects are a large contributor to toxicity from cell therapies and T cell engagers 40–43 . This QSP model thus presents a modeling framework to predict on‐target off‐tumor binding and cytokine production for CD3 bispecifics.…”

“…This finding is consistent with current scientific understanding: on-target off-tumor effects are a large contributor to toxicity from cell therapies and T cell engagers. [40][41][42][43] This QSP model thus presents a modeling framework to predict on-target off-tumor binding and cytokine production for CD3 bispecifics. This QSP model can be a powerful tool to assist in dose selection with increased confidence in safety outcomes.…”

Current status and future perspectives of bispecific antibodies in the treatment of lung cancer

“…Using anti-cytokine antibodies and modifying bsAbs by changing or deleting the Fc region are feasible measures to reduce CRS. [ 86 ] In addition, the influence of immunogenicity on the efficacy and safety of bsAbs cannot be ignored. Immunogenicity assessment as early as possible before clinical studies and development of more comprehensive detection methods may help overcome immunogenicity.…”

“…Whether corticosteroids might inhibit the anti-tumor efficacy of bsAbs needs further investigation. Using anti-cytokine antibodies and modifying bsAbs by changing or deleting the Fc region are feasible measures to reduce CRS [86] . In addition, the influence of immunogenicity on the efficacy and safety of bsAbs cannot be ignored.…”

Immuno-cardio-oncology: Killing two birds with one stone?

“…Pretreatment with anti-inflammatory drugs, like anti-IL-6R mAb, new gene-editing technologies of ex vivo CAR T cell generation decreases this risk. In addition, next-generation of designed bispecific CD3-engager antibodies, targeting endogenous T cells to a defined target cell with high efficiency but limited side effects ( 98 ) opens new opportunities to use in cancer and non-cancer diseases without enhanced risk of CVD or even to treat CVD/heart failure by immune targeting ( 99 ).…”