Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

Abstract

T-cell Bispecific Antibodies (TCBs) elicit anti-tumor responses by cross-linking T-cells to tumor cells and mediate polyclonal T-cell expansion that is independent of T-cell receptor specificity. TCBs thus offer great promise for patients who lack antigen-specific T-cells or have non-inflamed tumors, which are parameters known to limit the response of checkpoint inhibitors. The current study deepens the understanding of TCB mode of action and elaborates on one of the adaptive resistance mechanisms following its treatment in vivo in humanized mice and syngeneic pre-clinical tumor models. Single-agent TCB treatment reduced tumor growth compared with controls and led to a 2–10-fold increase in tumor-infiltrating T-cells, regardless of the baseline tumor immune cell infiltration. TCB treatment strongly induced the secretion of CXCL10 and increased the frequency of intra-tumor CXCR3+ T-cells pointing to the potential role of the CXCL10-CXCR3 pathway as one of the mechanisms for T-cell recruitment to tumors upon TCB treatment. Tumor-infiltrating T-cells displayed a highly activated and proliferating phenotype, resulting in the generation of a highly inflamed tumor microenvironment. A molecular signature of TCB treatment was determined (CD8, PD-1, MIP-a, CXCL10, CXCL13) to identify parameters that most robustly characterize TCB activity. Parallel to T-cell activation, TCB treatment also led to a clear upregulation of PD-1 on T-cells and PD-L1 on tumor cells and T-cells. Combining TCB treatment with anti-PD-L1 blocking antibody improved anti-tumor efficacy compared to either agent given as monotherapy, increasing the frequency of intra-tumoral T-cells. Together, the data of the current study expand our knowledge of the molecular and cellular features associated with TCB activity and provide evidence that the PD-1/PD-L1 axis is one of the adaptive resistance mechanisms associated with TCB activity. This mechanism can be managed by the combination of TCB with anti-PD-L1 blocking antibody translating into more efficacious anti-tumor activity and prolonged control of the tumor outgrowth. The elucidation of additional resistance mechanisms beyond the PD-1/PD-L1 axis will constitute an important milestone for our understanding of factors determining tumor escape and deepening of TCB anti-tumor responses in both solid tumors and hematological disorders.

An optimal antitumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers

“…The synergistic effect of combination therapy of CEA-TCB and PD-L1 antibody was observed in the in vivo humanized model [ 22 ] as well as in the clinic trials [ 11 ], it would be interesting to evaluate enhanced efficacy using a suboptimal dose of CEA/CD3-v2 in combination with atezolizumab (anti-PD-L1) against LS174T tumor cells that are positive for both CEA and PD-L1 (data not shown) in hPBMC grafted-NCG model. The monotreatment of CEA/CD3-v2 (0.3 mg/kg) or atezolizumab (20 mg/kg) reduced TGI% by 66.83% and 43.05%, respectively, compared with vehicle control ( Fig.…”

“…CEA is an important biomarker in many tumors including CRC, and represents a promising tumor antigen for solid tumors. Roche’s CEA-TCB bsAb has shown initial proof of concept as monotherapy, as well as in combination with anti-PDL1 in mCRC [ 11 , 22 ]. Here, we present a potent CD3 affinity-tuned t-TCE molecule with bivalent tumor targeting and functionally monovalent CD3 binding.…”

Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

“…The 2 + 1 antibody format, often utilized in the context of TCBs, has been used for various bispecific antibodies and applications (45,48,50,(70)(71)(72)(73). These TCBs share a common architecture, as the CD3-engaging Fab fragment is located directly on the Fc, Nterminally fused to an additional Fab arm.…”

Targeting the tumor microenvironment in chronic lymphocytic leukemia

“…T-cell bispecific antibodies combined with an anti-PD-L1 antibody showed enhanced antitumor efficacy compared to either given alone in a solid cancer mouse model. 105 Furthermore, a recent CLL murine study demonstrated that anti-PD1 ICB combined with inhibition of the immune checkpoint receptor lymphocyte-antigen gene 3 (LAG3) was able to decrease tumor load significantly, while either as monotherapy had little effect. 106 Thus, developing combination immunotherapy could represent a powerful strategy for deepening targeted drug (e.g., BTK inhibitor-and/or venetoclax)-induced responses and working towards curative therapy in CLL.…”