Adoptive cell therapy with genetically engineered T-cells is providing a new approach to treat a variety of lymphomas, leukemias and solid tumors. For most cancer patients their T-cells, an important anti-tumor component of the immune system, become tolerant to tumor cell antigens. The inability of the immune system to respond to tumors has remained a major barrier to immune-mediated anti-cancer therapies, but novel modifications to patients’ T-cells promise to overcome this problem.
In adoptive T-cell therapy, patients’ T-cells are isolated, stimulated to proliferate, and engineered to express a chimeric antigen receptor (CAR). The CAR specifically recognizes a tumor antigen and is capable of signaling the T-cell to proliferate and mount a cytotoxic response against the tumor.
A recent pilot study by Drs. Brian Till, Oliver Press and colleagues in the Clinical Research Division has combined recent advances in genetic engineering of T-cells with pre-transfer lymphodepletion to treat non-Hodgkin lymphoma patients. In this study, T-cells from three patients with relapsed indolent B-cell lymphomas were expanded and engineered to express a CAR recognizing CD20, a cell surface protein expressed on the patients’ B-lineage tumor cells. In addition, the intracellular portion of the CAR contained the CD28 and CD137 co-stimulatory domains, a maneuver that has recently been shown to enhance T-cell activity compared to earlier generations of T-cell therapies. The inclusion of multiple co-stimulatory domains increased T-cell expansion and cytokine production in vitro, and was expected to produce better anti-tumor responses in vivo. Prior to T-cell transfer, patients were treated with cyclophosphamide chemotherapy to cause lymphodepletion, with the goal of improving engraftment of the transferred T-cells. Patients were then followed for the presence of the modified T-cells and their anti-tumor effects.
The treatment was generally well tolerated, and was associated with possible anti-tumor effects in all three patients. Similar patient groups not receiving adoptive T-cell therapy generally progress within 6 months; however, two patients in this study remained progression-free for one and two years following treatment. The third patient had a partial remission, but relapsed one year after the T-cell transfers. The engineered T-cells were detected in blood up to one year, and no host responses against the engineered T-cells were detected. Thus, this pilot study supports recent modifications to CAR design and pretreatment lymphodepletion as promising anti-tumor immuno-therapies. Ongoing developments in ex vivo culturing and T-cell modifications, which are aimed at establishing greater CAR surface expression, T-cell proliferation and effector function in vivo, are hoped to provide more durable anti-tumor T-cell responses in future patients.
Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Rautitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. DOI: 10.1182/blood-2011-10-387969.