Project 459808

Discoveries in the field of immunotherapy have been rapidly accelerating, entering the forefront as a leading area of cancer research and delivering novel therapeutics that have revolutionized the treatment landscape for most liquid and solid malignancies such as Multiple Myeloma (MM) and Small Cell Lung Cancer (SCLC). These breakthrough treatments including chimeric antigen receptor (CAR) T cells, which largely harness patients' adaptive immunity, have already shown very encouraging results in heavily pre-treated patients. However, responses to these immunotherapies are not universal and durable and resistance does invariably occur due to the presence of a tolerant tumor microenvironment (TME). T cells can be endowed with specificity for tumor cells through genetic modification but remain poorly prepared to withstand the physical and immunological barriers imposed by the TME. The central hypothesis in this project is that CAR-T cells can be instructed by advanced genetic engineering to either remove (seek & destroy) or modify (seek & modulate) negative influences in the TME, thereby 'paving their own way' for delivering antitumor efficacy and preserving the conceptual appeal of CAR-T therapy as a 'stand-alone (no combination therapy required), single-shot (no repeat)' treatment. The objectives of the study are: 1. To determine key components in the MM and SCLC TME as biomarkers and targets for SmartCAR-T engineering using advanced multi-omics approaches and imaging techniques. 2. To develop SmartCAR-Ts which destroy or modulate the TME in MM and SCLC. 3. To determine the gain in antitumor function of SmartCAR-T cells. We anticipate that SmartCAR-T cells equipped with seek & destroy or seek & modulate functions will confer superior and more durable anti-tumor reactivity. The project will deliver effective therapies for ´hard-to-treat' cancers, determine key factors in the TME and provide a platform that can be rapidly adjusted to other tumor types.