Immunotherapy has dramatically improved outcomes for cancer patients. A single injection of gene-modified immune cells equipped with a therapeutic receptor that targets cancer cells can cure several cancer types originating from blood cells. However, the success of gene therapy has not yet been extended to other cancer types, where two major challenges are i) difficulties in identifying safe target molecules and efficacious immune receptors that recognize them, and ii) immune-suppressive mechanisms in the tumor. The Precision Immunotherapy Alliance (PRIMA) will use the immune system of healthy donors to overcome these bottlenecks and extend cell-based immunotherapy to a range of blood and solid cancers. Thereby novel categories of therapeutic targets that are shared among large numbers of patients can be exploited. Other targets for precision immunotherapy will be identified by a combination of sophisticated computational analysis tools and experiments that identify cell types and how they interact in the tumor. A combination of gene-modified immune cells and new agents that overcome tumor defense mechanisms may radically improve cancer therapy. Promising therapeutic modalities will be scaled-up for first-in-man clinical trials in a new infrastructure for advanced cell and gene therapy.
Immunotherapy has transformed outcomes for patients with cancer. A single infusion of genetically modified T cells expressing chimeric antigen receptors (CAR-T cells) can lead to cures for advanced disease. However, the success of cell therapy is largely limited to B-cell malignancies. Major challenges to extend cell-based immunotherapy to other types of cancer include i) lack of cell surface molecules that can be safely targeted by CARs and evoke efficient T cell responses, and ii) immune exclusion and immune suppression in the tumor microenvironment (TME), leading to therapy failure. The Precision Immunotherapy Alliance (PRIMA) makes use of donor-derived immunity to overcome these bottlenecks and thereby extend cell-based immunotherapy to a wide range of hematological and solid cancers. This opens the door to novel categories of therapeutic targets that are shared among large numbers of patients but ignored by the patient immune system. Targets identified by bioinformatics combined with mass spectrometry will be pursued for generation of reactive, donor-derived T-cell receptors (TCRs). We will use multi-dimensional spatial imaging and single-cell RNA sequencing to identify immunosuppressive elements in the TME and translate results into design of novel protein-based biologics with fine-tuned binding and transport properties optimal for anti-cancer treatment. Cytotoxic T- and natural killer (NK) cells engineered to express TCRs will be used in disease-relevant models to determine efficacy and safety alone or in combination with TME modulating strategies. Finally, multi-modal gene-editing in inducible pluripotent stem cells (iPSCs) will be used to develop universal off-the-shelf therapeutic cells with tailored specificity, increased potency, and in vivo persistence. Promising therapeutic modalities will be scaled-up for first-in-man clinical trials in a new infrastructure for advanced cell therapy.