Periodic Reporting for period 2 - RARITY (RAtional design of canceR ImmunoTherapY: one size does not fit all)
Berichtszeitraum: 2021-06-01 bis 2022-11-30
Cancer is the second leading cause of mortality worldwide, being responsible for nearly 10 million deaths per year. Alarmingly, the incidence of some cancers is also on the rise and, in particular, in younger adults. A such, the societal (and economic) impact of this disease is astronomic and ever increasing. These data underline the pressing need for the development of effective cancer therapies that decrease the societal burden that is imposed by cancer.
Immunotherapy makes use of molecules and cells from our immune system and has, in recent years, delivered major breakthroughs in the treatment of cancer. Patients diagnosed with previously untreatable cancers like advanced lung cancer or melanoma may now benefit from therapies that activate the immune system to fight and eliminate cancer cells. Nevertheless, the majority of cancer-related deaths still cannot be prevented by current immunotherapies as these are not effective in all cancer patients. On the other hand, we have only recently started to uncover the full potential of the immune system to deal with cancer which opens promising avenues for future treatments.
RARITY aims at providing innovative solutions for the development of effective immunotherapies that can be applied to cancer patients who cannot benefit from current immunotherapeutic approaches. Objectives of the project include: (1) the optimal exploitation of a cancer patient’s naturally-occurring T cells for their treatment, (2) the uncovering of novel targets in cancer cells that can be recognized and attacked by the immune system and, finally, (3) the discovery and characterization of novel immune cells with anti-cancer activity. Altogether, this project aims at increasing the diversity and efficacy of the cancer immunotherapy “toolbox” so that immunotherapy becomes increasingly applicable for the treatment of cancer.
Immunotherapy makes use of molecules and cells from our immune system and has, in recent years, delivered major breakthroughs in the treatment of cancer. Patients diagnosed with previously untreatable cancers like advanced lung cancer or melanoma may now benefit from therapies that activate the immune system to fight and eliminate cancer cells. Nevertheless, the majority of cancer-related deaths still cannot be prevented by current immunotherapies as these are not effective in all cancer patients. On the other hand, we have only recently started to uncover the full potential of the immune system to deal with cancer which opens promising avenues for future treatments.
RARITY aims at providing innovative solutions for the development of effective immunotherapies that can be applied to cancer patients who cannot benefit from current immunotherapeutic approaches. Objectives of the project include: (1) the optimal exploitation of a cancer patient’s naturally-occurring T cells for their treatment, (2) the uncovering of novel targets in cancer cells that can be recognized and attacked by the immune system and, finally, (3) the discovery and characterization of novel immune cells with anti-cancer activity. Altogether, this project aims at increasing the diversity and efficacy of the cancer immunotherapy “toolbox” so that immunotherapy becomes increasingly applicable for the treatment of cancer.
In the first aim of the project, we proposed to develop advanced T cell therapies by characterizing, isolating, and converting patient’s cancer-specific T cells into high-quality therapeutic products. To this end, it was essential to identify cellular markers that allows to separate cancer-specific T cells from total T cell populations. Recently, we proposed two markers (proteins) that pinpoint T cells with anti-cancer potential in colorectal cancer patients (manuscript submitted for publication). This observation is of great importance as it can support the development of improved T cell-based immunotherapies. The latter application requires that T cells are expanded in the lab before being administered back to the patients. Unfortunately their manipulation outside the patient’s body often implies loss of functional characteristics that are important for T cell activity. To address this we are developing culturing procedures that preserve (or enhance) the functional properties of T cells when expanded in the laboratory (work under development).
To address the second aim of the project, we employed advanced genomic techniques to discover novel targets in cancer cells that can be recognized and potentially used as triggers for the activity of immune cells (T cells) against cancer cells. Beyond what is currently considered to be the focus of immune recognition on cancer cells, we identified several molecules with the potential to constitute new targets for T cells and, importantly, for immunotherapy. We are currently in the process of validating and expanding our findings to additional patients to confirm their significance.
In aim 3, we proposed to identify immune cell populations that are currently underappreciated regarding their role in anti-cancer immune responses but which, nevertheless, carry high potential for application in a therapeutic context. Excitingly, we discovered that an unconventional type of T cells, gamma-delta T cells play an important role in the recognition of cancers that have escaped immune recognition by conventional T cells. Moreover, we demonstrate that gamma-delta T cells are likely to be involved in mediating responses to cancer immunotherapy in some cancer patients (prepublication, de Vries et al. bioRxiv 2021). This groundbreaking findings opens new avenues for the exploitation of gamma-delta T cells as a therapeutic tool.
To address the second aim of the project, we employed advanced genomic techniques to discover novel targets in cancer cells that can be recognized and potentially used as triggers for the activity of immune cells (T cells) against cancer cells. Beyond what is currently considered to be the focus of immune recognition on cancer cells, we identified several molecules with the potential to constitute new targets for T cells and, importantly, for immunotherapy. We are currently in the process of validating and expanding our findings to additional patients to confirm their significance.
In aim 3, we proposed to identify immune cell populations that are currently underappreciated regarding their role in anti-cancer immune responses but which, nevertheless, carry high potential for application in a therapeutic context. Excitingly, we discovered that an unconventional type of T cells, gamma-delta T cells play an important role in the recognition of cancers that have escaped immune recognition by conventional T cells. Moreover, we demonstrate that gamma-delta T cells are likely to be involved in mediating responses to cancer immunotherapy in some cancer patients (prepublication, de Vries et al. bioRxiv 2021). This groundbreaking findings opens new avenues for the exploitation of gamma-delta T cells as a therapeutic tool.
In summary, this project has delivered, beyond the state of the art, (1) specific markers that can be used to isolate T cells with optimal anti-cancer activity for reconversion into high-quality T cell products, (2) promising clues regarding novel targets that can be used to stimulate immune responses against cancer cells and, (3) the demonstration and discovery, for the first time, that gamma-delta T cells are involved in the response to immune checkpoint blockade therapies in a specific population of (colorectal) cancer patients. All of the previous findings will make a contribution to move the field of cancer immunotherapy beyond the state-of-the-art.
Questions still to be addressed as the project moves forward include:
- How to optimally manipulate T cell in vitro to preserve their functional characteristics?
- How to reliably identify unconventional antigens/proteins in cancer cells that can be targeted in the context of immunotherapy?
- What is the role of additional immune cell subsets that have been identified by our project as being involved in anti-cancer immune responses (beyond gamma-delta T cells).
At the end of the project, the following results are expected:
- Markers for the specific isolation of T cells with anti-cancer activity from patients will allow the conversion of naturally-occurring T cells in tumors into therapeutic T cell products. Importantly, culturing conditions will be established that optimize the growth of T cells in the lab so that they preserve their functional characteristics.
- Novel targets for the activation of immune responses against cancer cells will be identified and could potentially be used in the context of vaccination for the stimulation of a patient’s immune system against their cancer.
- Our knowledge regarding the role of additional immune cell subsets in mediating anti-tumor immune responses will be considerably expanded. Importantly, may have already provided a major breakthrough as it related the activity of gamma-delta T cells in cancer patients to immunotherapy responses.
Questions still to be addressed as the project moves forward include:
- How to optimally manipulate T cell in vitro to preserve their functional characteristics?
- How to reliably identify unconventional antigens/proteins in cancer cells that can be targeted in the context of immunotherapy?
- What is the role of additional immune cell subsets that have been identified by our project as being involved in anti-cancer immune responses (beyond gamma-delta T cells).
At the end of the project, the following results are expected:
- Markers for the specific isolation of T cells with anti-cancer activity from patients will allow the conversion of naturally-occurring T cells in tumors into therapeutic T cell products. Importantly, culturing conditions will be established that optimize the growth of T cells in the lab so that they preserve their functional characteristics.
- Novel targets for the activation of immune responses against cancer cells will be identified and could potentially be used in the context of vaccination for the stimulation of a patient’s immune system against their cancer.
- Our knowledge regarding the role of additional immune cell subsets in mediating anti-tumor immune responses will be considerably expanded. Importantly, may have already provided a major breakthrough as it related the activity of gamma-delta T cells in cancer patients to immunotherapy responses.