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

Abstract

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.

Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive‐stage small cell lung cancer: A multicentre, randomised, double‐blind, placebo‐controlled Phase II trial

“…In theory, trilaciclib has the potential to improve antitumour efficacy by enabling maintenance of chemotherapy dse intensity, while simultaneously facilitating a more favourable, and less damaged, immune system. Preclinical data showed that the addition of trilaciclib prior to chemotherapy plus ICI regimens, including both PD‐L1 and PD‐1 inhibitors, enhanced antitumour response and OS through the modulation of T‐cell proliferation and the tumour immune microenvironment, and increased effector function 18,20,50 . Flow cytometry and TCR immunosequencing data from this clinical study are consistent with these findings.…”

“…In addition, high levels of clonal expansion were associated with improved PFS and numerically longer median OS. Taken together, the data suggest that the addition of trilaciclib at least preserves, if not enhances, T‐cell function during treatment with E/P or E/P/A 18 …”

“…19 In addition to protecting lymphocyte populations and increasing immune activation through differential T-cell recovery, trilaciclib and other CDK4/6 inhibitors have been shown to enhance antitumour responses through other mechanisms in preclinical models, including enhanced T-cell activation through modulation of nuclear factor of activated T-cell activity and upregulation and stabilisation of PD-L1 expression on tumour cells, resulting in increased sensitivity to ICI. 18,20 Preclinically, the addition of trilaciclib to chemotherapy/ICI combinations has been shown to enhance and prolong the duration of the antitumour responses, providing a rationale for combining trilaciclib with chemotherapy/ICI regimens in patients with cancer. 18 Data from a randomised, double-blind, placebo-controlled Phase II trial of trilaciclib administered prior to E/P therapy in patients with newly diagnosed ES-SCLC showed myelopreservation benefits across multiple haematopoietic lineages (neutrophils and red blood cells [RBCs]) compared with placebo, with patients requiring fewer supportive care interventions and chemotherapy dose reductions.…”

Mechanisms of small cell lung cancer metastasis

“…In SCLC, the connections between immune cells and metastases have not yet been carefully explored, but emerging evidence suggests that innate immune cells may affect the ability of SCLC cells to metastasize to the liver (Sato et al , 2013; Best et al , 2020). In this regard, it is unknown whether strategies such as inhibition of CDK4/6 kinases to protect immune cells from chemotherapy in SCLC patients (He et al , 2017; Lai et al , 2020) will have effect on metastasis. Future studies will uncover the compendium of immune cell types and interactions that influence SCLC metastases, which could uncover promising avenues for the development of therapies against SCLC metastases.…”

CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory

“…Using CDK4/6 inhibitors as a preconditioning tool, rather than a combination therapy, may mitigate this toxicity risk. Further, as CDK4/6 inhibition compromises expansion of CD8+ T cells, using CDK4/6 inhibition as a priming tool may also be a more efficacious strategy as is removes the potential complication of restricted T cell expansion following ICB administration, which is likely to occur if CDK4/6 inhibition is continuously co- sufficient to promote anti-tumor immunity (45,46), and here we demonstrate a novel strategy for employing CDK4/6 inhibitors to enhance the efficacy of ICB, without the toxicity risk associated with combination approaches.…”