The Riddell lab is working to define principles for successful adoptive transfer of genetically modified, cancer-targeting T cells by:
A major focus of the Riddell lab is to identify and design receptors that target tumor-associated antigens. The lab has designed CARs specific for CD19 in lymphoid malignancies, B cell maturation antigen (BCMA) in myelomas, and the orphan receptor tyrosine kinase, ROR1, which is commonly overexpressed by chronic lymphocytic leukemia, mantle cell lymphoma, breast cancer, lung cancer, and ovarian cancer. CARs targeting each of these molecules have been advanced to clinical trials. Dr. Riddell’s team has developed novel CAR designs that have improved signaling qualities or that incorporate Strep-tag II sequences that can be used to tailor CAR spacer length, and to identify, rapidly purify and selectively expand transduced cells.
Members of the Riddell lab are also identifying cancer ‘neoantigens’ that could serve as targets for engineered T cells. Neoantigens are encoded by tumor-specific mutations and gene fusions present in cancer cells, and are ideal targets for T cell immunotherapy because they are not expressed by normal cells. The Riddell team recently reported the identification of a MHC class II-restricted T cell receptor specific for the BRAF V600E mutation, and has identified TCRs specific for other oncogenic mutations.
Synthetic biology is emerging as a major strategy for designing new cellular medicines. The basic concept underlying the design of synthetic CARs that redirect T cell specificity is to link an extracellular ligand recognition domain, typically a single-chain variable fragment (scFv) that is specific for a molecule on the cancer cell surface, to intracellular signaling modules. Most clinical used CARs use a CD3z endodomain to induce T cell activation upon antigen binding, plus one or more costimulatory molecules (derived from CD28, 4-1BB, OX40, and/or ICOS). The design of synthetic CARs is largely empiric. The Riddell lab is examining how structural constraints imposed by T cell:target cell interactions, scFv affinity and spacer length affect anti-tumor function. Lab members are also studying how costimulatory domain signaling and novel signaling modules impact T cell effector function and fate.
The therapeutic efficacy of adoptive T cell therapy has been shown to correlate with the ability of transferred T cells to proliferate in response to antigen, migrate to tumor sites, exhibit effector function and persist in vivo. T cells exist in functionally and phenotypically distinct naïve, memory and effector subsets that collectively contribute to eradicating pathogens and tumors, and provide life-long memory to deal with subsequent onslaughts. Riddell lab members have been at the forefront of determining which of these different subsets of T cells have the properties necessary to be highly effective in treating cancer, and the lab has developed cell selection platforms to isolate optimal T cell subsets for genetic engineering. This work led to the first human trial of CD19 CAR T cells of defined subset composition, which revealed dose/response and dose/toxicity relationships that improve the therapeutic index. Riddell’s team is now investigating new approaches to improve the intrinsic anti-tumor capacities of CAR T cells, both by manipulating cell differentiation and introducing genes that confer novel functions.
The Riddell lab uses a variety of preclinical animal models of cancer to evaluate new strategies to improve adoptive T cell therapy including human tumor xenografts in immunodeficient mice and syngeneic and orthotopic models in immunocompetent mice, in which tumor cells are implanted in the originating tissue. Notably, the lab has established an authochthonous (native) model of lung adenocarcinoma fin which to systematically examine the barriers to effective T cell therapy in solid tumors arising after oncogene activation. Lab members use these models to evaluate safety, new tumor-targeting receptors and cell engineering approaches, and small molecules that in combination with T cells improve antitumor efficacy. Separately, the lab is testing systemic personalized cell based cancer vaccines that are designed to elicit or augment immunity to tumor-specific neoantigens.
The overall objective of the Riddell lab is to translate novel adoptive T cell therapies targeting tumor-associated antigens from laboratory studies to clinical trials that assess safety and antitumor efficacy in patients. Trials are conducted with state of the art immunologic monitoring to derive insights that improve patient outcomes. The CD19-specific CAR T cell therapy developed in the Riddell lab has benefited many individuals with B cell leukemias and lymphomas, and this approach has been commercialized for treatment of these cancers. Many patients still do not respond to therapy or relapse months to years after therapy, and ongoing work is evaluating strategies to increase response rates, reduce relapse rates and prevent toxicity in patients receiving CD19 CAR T cells. We are committed to broadening the applications of T cell therapy to more patients with cancer and have developed phase I clinical trials evaluating the safety and efficacy of CAR T cell therapy targeting BCMA for patients with multiple myeloma, and targeting ROR1 for patients with ROR1-positive refractory B cell malignancies, non-small cell lung cancer, or triple-negative breast cancer