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.
Highlights
Targeting T-cells with antibodies that directly enhance T-cell activity, including the checkpoint inhibitory molecules (CPIs) programmed death receptor 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic lymphocyte activated antigen 4 (CTLA4) has become an established approach in clinical practice [1,2,3]
The current study was undertaken to expand our understanding of cellular and molecular features associated with T-cell Bispecific Antibodies (TCBs) activity and to address one of the key adaptive resistance mechanisms related to TCB activity, namely PD-1/PD-L1 axis upregulation, to what has been described for checkpoint inhibitors [30]
These comprised hematopoietic stem cell humanized NOG mice bearing human gastric and pancreatic tumors and immunocompetent human CEA transgenic C57BL/6J mice bearing a murine colorectal cancer tumor line (MC38) or crossed with genetically modified CEA424-SV40 TAg transgenic mice that spontaneously develop gastric tumors in the pyloric region. The former represent a hyper-mutated and highly inflamed form of colorectal cancers (MSIhi CRC) [49] transfected to stably express human CEA (MC38-hCEA), the latter an aggressive form of murine gastric cancer with immune desert phenotype, which is poorly responsive to cancer immunotherapy treatment (Steinhoff N et al, in preparation)
Summary
Targeting T-cells with antibodies that directly enhance T-cell activity, including the checkpoint inhibitory molecules (CPIs) programmed death receptor 1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic lymphocyte activated antigen 4 (CTLA4) has become an established approach in clinical practice [1,2,3]. Antibodies to checkpoint molecules have gained broad approval in various tumor indications for the treatment of advanced cancer types such as metastatic melanoma, advanced non-small cell lung cancer, or renal cell carcinoma [4]. Despite these advances, obstacles still exist including the inability to predict treatment efficacy and patient response, the need for additional biomarkers, the development of primary and secondary resistance to cancer immunotherapies, the lack of clinical study designs that are optimized to determine efficacy and toxicity (and their relationship), and high treatment costs [5]. Due to the increase of intra-tumor T-cell infiltration upon treatment [8,9,10], TCBs offer great promise in patients that lack the baseline antigen-specific T-cells (or any type of T-cells, the so called immune desert tumors), which is thought to render responses to checkpoint inhibition less likely [5]
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