G1T28, a CDK4/6 inhibitor, preserves T lymphocyte function from damage by cytotoxic chemotherapy

Roberts, Patrick; He, Songqing; Schvartsman, G.; Patil, Tejas; Sorrentio, J.; Bisi, John E.; Hoyer, R.; Schuster, Stephen J.; Strum, Jay C.; Heymach, John V.; Ferrarotto, Renata; Sharpless, Norman E.; Shapiro, Geoffrey I.; Malik, Rajesh

doi:10.1016/s0959-8049(16)33026-x

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“…Consistent with the ability of trilaciclib to enhance or preserve effector T-cell function during exposure to chemotherapy, we have previously shown ex vivo stimulation of splenic T cells from animals treated with trilaciclib plus 5-FU resulted in the increased production of IFN-γ and IL-2 compared with 5-FU treatment alone. 34 Further investigation is needed to determine whether trilaciclib-mediated G1 arrest results in Treg depletion or apoptosis, or if transient proliferative arrest leads to the differentiation of Tregs into effector CD4 + T cells. In the current study, intratumor T-cell populations were defined using CD4 and CD8 cell surface markers only.…”

Section: Discussionmentioning

confidence: 99%

CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy

Lai

Sorrentino

Dragnev

et al. 2020

J Immunother Cancer

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BackgroundCombination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations.MethodsIn murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation.ResultsPreclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function.ConclusionsTransient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.

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Section: Discussionmentioning

confidence: 99%