Anti-tumor efficacy of a combination therapy with PD-L1 targeted alpha therapy and adoptive cell transfer of PD-1 deficient melanoma-specific human T-lymphocytes

Abstract

The optimization of adoptive transfer approaches of anti-tumor T cells requires both the functional improvement of the injected T cells and the modulation of the tumor microenvironment, favoring the recruitment of these T cells and their activation. We have recently shown the therapeutic benefit of two approaches tested individually in a melanoma model wich were on one hand the adoptive transfer of specific T cells deficient for the expression of the inhibitory receptor PD-1, and on the other hand PD-L1 targeted alpha therapy (TAT). In this study, we sought to investigate the efficacy of these two therapies combined, compared to each monotherapy, in order to evaluate the synergy between these two approaches, in the same melanoma model. Here we used melanoma-specific T-cell clones, previously validated for the edition of PDCD1 gene and with previously demonstrated superior anti-tumor activity than their wild-type counterparts, after adoptive transfer in NSG mice engrafted with PD-L1 expressing human melanoma tumors. We also used a previously validated TAT approach, using a 213 Bi-anti-human-PD-L1 mAb, alone or in combination with adoptive cell transfer, in the same mouse model. We confirmed previous results obtained with each monotherapy and documented the safety and the superior ability of a combination between the adoptive transfer of PD-1 deficient T cells and TAT targeting PD-L1 to control the growth of melanoma tumors in NSG mice. This study provides the first proof-of-concept of the efficacy of a combination therapy using TAT, adoptive cell transfer and genomic editing of IC-coding genes.

Mechanisms of Resistance and Strategies to Combat Resistance in PD-(L)1 Blockade

“…Another study utilized HER-2+ transgenic mice models to study the ef of CAR-T cells with and without PD-1 inhibition, and it was observed that the comb tion therapy improved the therapeutic efficacy of CAR-T-cells against solid cancers [ The synergy seen in the combination therapy is likely multifactorial, being a produ increased T-cell effector activity and other effects, such as enhanced T-cell survival [1 Investigations into the gene editing of CAR-T cells have revealed that PD1-knoc CAR-T cells are a clinically efficacious alternative to combination therapy. Specifical was observed in murine models that editing the PD1 gene on tumor-specific T-cel reduce the expression of PD-1 resulted in a significant delay in tumor growth follow administration to PD-L1 overexpressing tumors [107,108]. Further data supports t findings, in that PD-1 deficient CAR-T cells showed significantly better antitumor effi than wild-type CAR-T cells [109][110][111].…”

“…Investigations into the gene editing of CAR-T cells have revealed that PD1-knockout CAR-T cells are a clinically efficacious alternative to combination therapy. Specifically, it was observed in murine models that editing the PD1 gene on tumor-specific T-cells to reduce the expression of PD-1 resulted in a significant delay in tumor growth following administration to PD-L1 overexpressing tumors [107,108]. Further data supports these findings, in that PD-1 deficient CAR-T cells showed significantly better antitumor efficacy than wild-type CAR-T cells [109][110][111].…”

NIVO-TIL: Combination anti-PD-1 and adoptive T-cell transfer in metastatic melanoma: a proof of concept

“…The optimization of adoptive transfer of anti-tumor T cells requires both the functional improvement of the injected T cells and the modulation of the tumor microenvironment, favoring the recruitment of these T cells and their activation. Marotte et al [13] have investigated and demonstrated the safety and the superiority of a combination between the adoptive transfer of PD-1 de cient T cells and targeted alpha therapy (TAT) PD-L1 to control the growth of melanoma tumors in NSG mice (NOD scid gamma mouse, i.e., immunode cient laboratory mice). Thus, they provide the rst proof-of-concept of the e cacy of a combination therapy using TAT, adoptive cell transfer and genomic editing of IC-coding genes.…”

Lipid Nanoparticles for mRNA Delivery to Enhance Cancer Immunotherapy

“…ACT is an important method for immune cell therapy of infiltrative tumors, using the antitumor characteristics of lymphocytes to remove primary and metastatic tumor cells [ 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ]. Autologous (patient’s own) or allogeneic (donor’s) tumor-infiltrating lymphocytes (TILs) are activated in vitro, expanded to a certain number, and reinfused into the patient [ 118 , 119 , 120 , 121 ].…”