Project 4
Despite innovative combined therapeutic approaches consisting of chemoradiotherapy and immune checkpoint inhibitors, the successful treatment of advanced solid tumors continues to pose a major clinical challenge. There remains an urgent need to to develop new targeted immunotherapeutic approaches that target tumor-specific biomarkers and identify biomarkers that reliably predict which patients are most likely to respond to a particular therapy.
The Multhoff group has identified the stress-inducible molecular chaperone Hsp70 as a tumor-specific recognition structure on the cell surface of a large number of different, highly aggressive solid tumors. The group has also demosntrated that activation of NK cells with an Hsp70-derived peptide (TKD) in combination with low-dose IL-2 triggers cells to recognize and kill tumor cells expressing this membrane form of Hsp70. The safety and efficacy of this approach has been demonstrated in completed Phase I and Phase II clinical trials. In a pilot study, it has also been shown that a combination therapy consisting of membrane Hsp70 targeted NK cells and a second-line PD1 Immune Checkpoint Inhibitor therapy is well tolerated and significantly prolongs the survival.
Based on the sequence of a unique murine monoclonal antibody which recognizes membrane Hsp70, we have developed the first membrane Hsp70 CAR T cell which elicits cytolytic activity against membrane Hsp70 positive tumor cells in vitro. Using humanized sequences of this antibody, the proposed project will develop CAR expressing cytolytic NK and T cells targeting membrane Hsp70 using primary T and NK cells as well as GMP-compatible NK cell lines and test these in a range of in vitro and in vivo settings. The optimal CAR effector cell type will be further tested in combination with immune checkpoint inhibitors and developed for clinical use within the framework of this project.
It is known that the clinical translation of new therapies is more successful when there is a reliable biomarker which can identify and monitor potentially responsive patients. In this regard, tumor cells expressing membrane Hsp70 actively secrete microvesicle-associated Hsp70 into circulation, levels of which can be determined using the CE certified Hsp70-exo ELISA test developed by multimmune. Tumor patients have significantly increased levels of Hsp70 in the blood and it has been shown that the viable tumor mass correlates with the amount of Hsp70 in the blood. Levels can therfore be used as a surrogate measure of therapeutic response. For these reasons, the Hsp70-exo ELISA can be considered as a Companion Diagnostic for patient stratification and monitoring. The Hsp70-exo ELISA will be used to support the pre-clinical and clinical translational studies.
In summary, the innovative membrane Hsp70 targeted cell therapies that are to be developed in this project, combined with the availability of the Hsp70-exo Companion Diagnostic for patient startification and monitoring, have significant potential to deliver effective therapeutic options to the large proportion of patients having cancers expressing membrane Hsp70.
