Periodic Reporting for period 1 - ImmuneSynapsEngagers (Immune Synapse Engagement as a Novel Approach for Cancer Immunotherapy)
Periodo di rendicontazione: 2023-03-01 al 2025-08-31
Scientists have been exploring new ways to eradicate tumors, especially metastatic tumors resistant to standard-of-care therapy. One of the core hallmarks of cancer is avoiding immune recognition and destruction by the immune system. Understanding this process is crucial for developing effective cancer immunotherapy strategies. Therapeutic antibodies that target specific types of immune cells are an emerging modality that stimulates the immune system to combat cancer cells. However, current antibody-based immunotherapies have critical limitations, such as inadequate effectiveness, often limited to a subset of patients, severe side effects, and the development of unresponsiveness of the cancer cells to the therapy. In our laboratory, we focus on thoroughly deciphering dynamic immune cell-cancer cell interactions within the specific tumor microenvironment in response to immunotherapy. This body of knowledge is the framework of our research-to-therapy approach. For each study, we select either currently available monoclonal antibodies with reported clinical limitations or immune targets with unfulfilled clinical potential. The data generated on the immune-cancer crosstalk allows us to identify the functional immune circuits and understand how to enhance them selectively. We further advance this knowledge by employing cutting-edge laboratory techniques to develop improved forms of monoclonal antibodies that can precisely target active interactions between immune cells, thereby triggering a specific anti-tumor immune response. These unique antibodies possess the capability to overcome the current unattainable level of safety and potent anti-tumor immunity. In summary, the overall objective of our research is to provide new insights into the mechanisms of antibody-based immunotherapies and how to enhance therapeutic efficacy while limiting toxicity.
Impact: Our innovative approach of redesigning monoclonal antibodies with specially tailored modes of action has shown promising results in pre-clinical tumor-bearing mouse models. Our scientific achievements hold the potential for developing new therapeutic antibodies that exhibit potent anti-tumor and anti-metastasis effects with milder side effects, making them a safer and more effective treatment option for cancer patients.
Impact: Our innovative approach of redesigning monoclonal antibodies with specially tailored modes of action has shown promising results in pre-clinical tumor-bearing mouse models. Our scientific achievements hold the potential for developing new therapeutic antibodies that exhibit potent anti-tumor and anti-metastasis effects with milder side effects, making them a safer and more effective treatment option for cancer patients.
Under the scope of this EU-funded project, we performed two major preclinical studies in which we developed novel therapeutic antibodies that demonstrated superior efficacy compared to their parental versions.
1) Next-generation immune cell engagers
Checkpoint inhibitors represent a class of therapeutic antibodies that activate the immune system, primarily by engaging effector T cells, to combat cancer cells. The current checkpoint inhibitors typically target a single immune pathway; they do not adequately address the intricate cell-cell interactions of the immune system that eventually converge in producing specific immune response outcomes. Therefore, immunotherapy by checkpoint inhibitors is insufficient for potentiating an effective anti-tumor immunity in most cancers. We tackled this challenge by creating a novel bi-specific monoclonal antibody that engineers immune cell communication as a novel immunotherapeutic approach. On one hand, it acts as a checkpoint inhibitor that stimulates tumor-reactive T cells by targeting an immune pathway termed PD-1. On the other hand, it binds a subpopulation of immune cells termed conventional type 1 dendritic cells. These dendritic cells play a key role in cancer cell recognition and promoting PD-1-positive T cell-mediated activity. The interplay between these two immune cell subpopulations in the tumor microenvironment and tumor-draining lymph nodes has been found to be a crucial limiting factor for effective immunotherapy. We characterized this novel antibody in various tumor-bearing mouse models. We observed increased migration of dendritic cells towards the tumor-draining lymph nodes, increased infiltration of activated T cells into the tumor, as well as enhanced physical interactions between these two cell subpopulations. It enabled the reprogramming of the immune cell network towards a more pro-inflammatory, effective anti-tumor immunity. We observed superior tumor growth control and anti-metastasis effect compared to the respective checkpoint inhibitor. Improved efficacy was also observed in tumor models that are otherwise resistant to checkpoint inhibitors.
The manuscript of this study, titled “Bispecific dendritic-T cell engager potentiates antitumor immunity,” by Shapir Itai et al. was recently published in the prestigious journal Cell in 2024.
2) A redesigned antibody to enhance anti-tumor potency
The manuscript of this study, titled “Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote anti-tumor immunity,” by Avraham et al. is currently under review for publication
1) Next-generation immune cell engagers
Checkpoint inhibitors represent a class of therapeutic antibodies that activate the immune system, primarily by engaging effector T cells, to combat cancer cells. The current checkpoint inhibitors typically target a single immune pathway; they do not adequately address the intricate cell-cell interactions of the immune system that eventually converge in producing specific immune response outcomes. Therefore, immunotherapy by checkpoint inhibitors is insufficient for potentiating an effective anti-tumor immunity in most cancers. We tackled this challenge by creating a novel bi-specific monoclonal antibody that engineers immune cell communication as a novel immunotherapeutic approach. On one hand, it acts as a checkpoint inhibitor that stimulates tumor-reactive T cells by targeting an immune pathway termed PD-1. On the other hand, it binds a subpopulation of immune cells termed conventional type 1 dendritic cells. These dendritic cells play a key role in cancer cell recognition and promoting PD-1-positive T cell-mediated activity. The interplay between these two immune cell subpopulations in the tumor microenvironment and tumor-draining lymph nodes has been found to be a crucial limiting factor for effective immunotherapy. We characterized this novel antibody in various tumor-bearing mouse models. We observed increased migration of dendritic cells towards the tumor-draining lymph nodes, increased infiltration of activated T cells into the tumor, as well as enhanced physical interactions between these two cell subpopulations. It enabled the reprogramming of the immune cell network towards a more pro-inflammatory, effective anti-tumor immunity. We observed superior tumor growth control and anti-metastasis effect compared to the respective checkpoint inhibitor. Improved efficacy was also observed in tumor models that are otherwise resistant to checkpoint inhibitors.
The manuscript of this study, titled “Bispecific dendritic-T cell engager potentiates antitumor immunity,” by Shapir Itai et al. was recently published in the prestigious journal Cell in 2024.
2) A redesigned antibody to enhance anti-tumor potency
The manuscript of this study, titled “Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote anti-tumor immunity,” by Avraham et al. is currently under review for publication
The potential impact of our project results is the introduction of novel, improved therapeutic antibodies into oncological clinical studies. We acknowledge the limitations of current antibody-based immunotherapies, such as their limited real-world effectiveness. To address this medical need, we are utilizing cutting-edge technologies to enhance their therapeutic potential. Our approach goes beyond the state-of-the-art by not focusing on target optimization but rather on the optimization of antibody-dependent relay of immune cell activities. We continue to perform extensive pre-clinical research aimed at enhancing the therapeutic potential of additional antibody-based cancer immunotherapies. Further uptake and success can be ensured once clinical trials embark to test our novel therapeutic antibodies. We are collaborating with Teva Pharmaceuticals to pursue this translational path.