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

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...

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Autores principales: Sam, Johannes, Colombetti, Sara, Fauti, Tanja, Roller, Andreas, Biehl, Marlene, Fahrni, Linda, Nicolini, Valeria, Perro, Mario, Nayak, Tapan, Bommer, Esther, Schoenle, Anne, Karagianni, Maria, Le Clech, Marine, Steinhoff, Nathalie, Klein, Christian, Umaña, Pablo, Bacac, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735156/
https://www.ncbi.nlm.nih.gov/pubmed/33330050
http://dx.doi.org/10.3389/fonc.2020.575737
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author Sam, Johannes
Colombetti, Sara
Fauti, Tanja
Roller, Andreas
Biehl, Marlene
Fahrni, Linda
Nicolini, Valeria
Perro, Mario
Nayak, Tapan
Bommer, Esther
Schoenle, Anne
Karagianni, Maria
Le Clech, Marine
Steinhoff, Nathalie
Klein, Christian
Umaña, Pablo
Bacac, Marina
author_facet Sam, Johannes
Colombetti, Sara
Fauti, Tanja
Roller, Andreas
Biehl, Marlene
Fahrni, Linda
Nicolini, Valeria
Perro, Mario
Nayak, Tapan
Bommer, Esther
Schoenle, Anne
Karagianni, Maria
Le Clech, Marine
Steinhoff, Nathalie
Klein, Christian
Umaña, Pablo
Bacac, Marina
author_sort Sam, Johannes
collection PubMed
description 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.
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spelling pubmed-77351562020-12-15 Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity Sam, Johannes Colombetti, Sara Fauti, Tanja Roller, Andreas Biehl, Marlene Fahrni, Linda Nicolini, Valeria Perro, Mario Nayak, Tapan Bommer, Esther Schoenle, Anne Karagianni, Maria Le Clech, Marine Steinhoff, Nathalie Klein, Christian Umaña, Pablo Bacac, Marina Front Oncol Oncology 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. Frontiers Media S.A. 2020-11-30 /pmc/articles/PMC7735156/ /pubmed/33330050 http://dx.doi.org/10.3389/fonc.2020.575737 Text en Copyright © 2020 Sam, Colombetti, Fauti, Roller, Biehl, Fahrni, Nicolini, Perro, Nayak, Bommer, Schoenle, Karagianni, Le Clech, Steinhoff, Klein, Umaña and Bacac http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Sam, Johannes
Colombetti, Sara
Fauti, Tanja
Roller, Andreas
Biehl, Marlene
Fahrni, Linda
Nicolini, Valeria
Perro, Mario
Nayak, Tapan
Bommer, Esther
Schoenle, Anne
Karagianni, Maria
Le Clech, Marine
Steinhoff, Nathalie
Klein, Christian
Umaña, Pablo
Bacac, Marina
Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity
title Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity
title_full Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity
title_fullStr Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity
title_full_unstemmed Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity
title_short Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity
title_sort combination of t-cell bispecific antibodies with pd-l1 checkpoint inhibition elicits superior anti-tumor activity
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735156/
https://www.ncbi.nlm.nih.gov/pubmed/33330050
http://dx.doi.org/10.3389/fonc.2020.575737
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