Chimeric antigen receptors (CARs) are genetically engineered molecules linking an antigen binding domain, via spacer and transmembrane domains, to an intracellular signaling domain that triggers T cell activation. The specificity of a T cell can be redirected to tumor-associated antigens expressed on the cell surface of target cells by genetically engineering the T cell to express a CAR. Adoptive immunotherapy with CAR-modified T cells has emerged as a highly promising treatment for B cell malignancies. Our team, working with Dr. Oliver Press, conducted and published the first clinical trial testing CAR T cells as a treatment for lymphoma, demonstrating that it was a feasible and safe therapy. We also additionally conducted the first-in-human clinical trial using a 3rd generation CAR, which we tested in lymphoma patients and showed to be safe and with evidence of anti-tumor activity. More recently, we have developed an improved version of this therapy using a 3rd generation, fully human CD20 CAR in a lentiviral vector, which much more efficiently transfers the CAR gene to T cells than our previous methods. We have initiated a phase I/II clinical trial testing this new construct, which is currently enrolling patients and showing promising preliminary results.
While CAR T cell therapy is a highly effective and promising treatment for patients with a range of B cell malignancies, a significant subset of patients do not respond, and other patients relapse after an initial response. Some of the reasons for this appear to be due to differences in “fitness” of the starting T cells between patients, inhibition of CAR T cells through PD-1 or other checkpoint molecules, or loss of the target antigen. However, in most cases, the causes of resistance or relapse are not known. We are conducting in depth studies of CAR T cells and tumor specimens in patients treated on our CD20 CAR T cell trial, including high-dimensional flow cytometry, multiplex immunohistochemistry, and single-cell gene expression profiling, in order to gain understanding into the mechanisms by which tumors evade CAR T cells.
During our ongoing CD20 CAR T cell clinical trial, we initially manufactured CD4+ and CD8+ cells separately to be able to infuse at a 1:1 ratio. However, we found that the CD8+ cells did not expand well ex vivo, and clinical activity was minimal. We hypothesized that CD8+ cell expansion would be improved in the presence of help from CD4+ cells and that mixing these cells at a defined ratio at culture initiation would enable enhanced CD8+ cell expansion. We found that indeed CD8+ CAR T cells exhibit superior growth in mixed cultures with CD4+ cells, but we also discovered that CD8+ cell function, including proliferation, cytokine secretion, and in vivo anti-tumor activity, is also superior when these cells are manufactured in the presence of CD4+ cells. We found that CD8+ cells cultured with CD4+ cells also exhibit lower levels of exhaustion markers and higher levels of memory markers, and that these phenotypic differences are driven by distinct transcriptional programs. We are in the process of investigating the mechanisms by which ex vivo exposure to CD4+ cells leads to these biological differences in CD8+ cells, including a potential role for CD40-CD40L interactions.
As a clinical scientist, Dr. Till has contributed to the optimization of induction therapy and to our understanding of the role of stem cell transplantation in non-Hodgkin lymphoma, with a focus on mantle cell lymphoma (MCL). He is active with SWOG (formerly the Southwest Oncology Group), designing clinical trials with other investigators around the country as part of the National Cancer Institute intergroup mechanism. He reported the results of a phase II U.S. cooperative group trial testing the addition of bortezomib to R-CHOP therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma. He was also the SWOG chair of a study (E1411) for newly diagnosed patients with MCL testing the addition of bortezomib to bendamustine and rituximab induction, and lenalidomide to rituximab maintenance, and is the current SWOG chair of an ongoing study evaluating whether autologous stem cell transplantation can be omitted in younger, fit MCL patients who achieve a molecular complete remission after front-line chemotherapy.