Most solid tumors are heterogeneous and have an immunosuppressive tumor microenvironment (TME). These characteristics could be the reason why the therapeutic efficacy of T cell engagers (TCE) and chimeric antigen receptor (CAR)-T cell therapies in solid tumors is relatively limited compared to their performance in treating hematological malignancies.
Tumor heterogeneity involves diverse subclones with distinct genomic alterations and antigenic profiles, making it difficult for targeted therapies to uniformly eliminate all cancer cells. Additionally, it is widely recognized that intrinsic heterogeneous antigen expression and antigen escape during treatment can contribute to limited outcomes of molecular targeting therapies.
Meanwhile, the immunosuppressive environment is created by the recruitment of suppressive immune cells, which produce inhibitory factors including cytokines and immune checkpoint molecules. This complex ecosystem further hampers the immune system's ability to mount an effective response against solid tumors.
Unlike immune checkpoint inhibitors like anti-PD-1/PD-L1 antibodies that can invigorate intrinsic antigen recognition system of T cells, T cell based-therapy such as TCE and CAR-T may be susceptible to tumor heterogeneity and the suppressive TME. Along with direct T-cell recruitment to tumor sites, the accomplishment of alleviating immunosuppressive TME or overcoming heterogeneity, or both, could be the rational strategy to enhance the efficacy of conventional TCE and CAR-T therapy.
By understanding the intricate interplay between tumor cells, immune cells, and the TME, and by focusing on approaches that tackle tumor heterogeneity and/or improve the immunosuppressive environment, we can pave the way for the development of more effective immunotherapies for patients with solid tumors.
We are looking for technologies to improve the efficacy and/or enhance multifunctionality of multi-specific antibody or CAR-T as single agents. Our focus is on two key areas, 1) to alleviate the immunosuppressive tumor microenvironment (TME), and 2) to overcome heterogeneity of solid tumors by leveraging host immune responses against tumor neoantigens.
- Technologies for modulating the innate immune systems to induce T cell responses against heterogeneous solid tumors, such as innate immune activators and antigen spreading enhancers.
- Technologies for modifying the immunosuppressive TME to activate anti-tumor immunity, such as tumor-associated macrophages (TAM) reprogramming, and novel immune checkpoint inhibitors.
- Proposals should include a strong hypothesis and scientific rationale for how the technology will alleviate immunosuppression within the TME and/or activate the innate immune system to induce T-cell responses against heterogeneous tumors, accompanied by a plan to validate these effects in vivo.
- In vivo data demonstrating that the technology activates the innate immune system to induce T-cell responses against heterogeneous tumors.
- In vivo data demonstrating that the technology alleviates and/or converts immunosuppression within TME.
- Data demonstrating that the underlying mechanisms and/or targets of the technology are conserved between experimental models in animals and humans.
- Information on tumor specificity and organ specificity of target molecules and/or mechanisms.
- Technologies that act on the mechanism/targets of T cells to simply enhance T cell activity.
- Combination approaches that rely on the synergistic effects of different types of therapies (e.g. small molecule inhibitor in combination with a CAR-T therapy or multi-specific antibody).
At Daiichi Sankyo, we attach significant importance to working with academic institutions, startups and bioventure companies to discover new therapeutics in the place where hypotheses are brought and tested in order to expand possibilities for scientific innovation breakthrough. We build sustainable relationships with partner institutions and companies through open and fair alliance management and trust based on mutual respect as the foundation for effective collaborations. Our goal is to jointly create new value for patients by maximizing each other’s expertise and strengths.
https://www.daiichisankyo.com/rd/strategy_operations/open_innovation/
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