Gut microbiome and CAR-T therapy

Abstract

Considerable progress has been made in cancer therapeutics recently with targeted strategies that are efficacious and less toxic. Immunotherapy and chimeric antigen receptor (CAR) T-cells are increasingly being evaluated in a variety of tumors in the relapsed/refractory as well as frontline disease settings, predominantly in hematologic malignancies (HM). Despite impressive outcomes in select patients, there remains significant heterogeneity in clinical response to CAR T-cells. The gut microbiome has emerged as one of the key host factors that could potentially be modulated to enhance responses to immunotherapy. Several recent human studies receiving immunotherapy showed a significantly superior response and survival in patients with the more diverse gut microbiome. Currently, it is unknown if gut microbiota modulates anti-tumor responses to CAR T-cells. Based on molecular and immunological understanding, we hypothesize that strategically manipulating gut microbiota may enhance responses to CAR T-cells. In this review, we further discuss resistance mechanisms to CAR T-cells in HM, potential approaches to overcome resistance by harnessing gut microbiota and other related novel strategies.

Keywords: CAR T-cells; CRISPR/cas9; Dysbiosis; Gut microbiome; Immuno-oncology; Immunotherapy; TRUCKs.

Fig. 1

Gut microbiota mediates the differentiation of naïve T-cells either into pro-inflammatory Th17 or anti-inflammatory, Tregs. These effector T-cells then migrate to systemic circulation from mLN. Th17 boosts effector T-cells, mainly mediated via IL-17, whereas Tregs suppress effector T-cell function, mediated via IL-10. Specific gut taxa may potentially be harnessed to enhance CAR T-cell responses in several ways (figure’s left to right): By influencing pre-CAR conditioning; by using specific, narrow-spectrum antibiotics to deplete select, detrimental gut microbes; suppression of Foxp3+ Tregs and hence circumventing Treg-induced CAR T-cell suppression; upregulation of IL-6/STAT3 signature; direct activation of CAR T-cells (similar mechanism as that of endogenous T-cells)

Fig. 2

Butyrate produced by Akkermansia muciniphila would preferentially mount a pro-inflammatory immune response and suppress Tregs in the TME. This IL-12-mediated immune effector T-cell activation will boost ICI efficacy and secondarily enhance responses to CAR T-cells