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Genetic engineering of T-cells to benefit anti-tumor immunotherapy


(a) Schematic of anti-CD20 chimeric antigen receptor (CAR). (b) PET-CT scan of a cervical lymph node at baseline and 3 months after receiving anti-CD20 CAR T-cell infusions, showing the clinical response of a B-cell lymphoma patient to the new ‘third generation’ CD20-specific adoptive immunotherapy.
J. Schoenborn and modified from manuscript

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.

Science Spotlight Editors
From the left: Science Spotlight editors Yiting Lim (Basic Sciences), Kyle Woodward (Clinical Research), Nicolas Chuvin (Human Biology), Maggie Burhans (Public Health Sciences) and Brianna Traxinger (Vaccine and Infectious Disease) Photo by Robert Hood / Fred Hutch

EDITORS

Yiting Lim
Basic Sciences Division

Nicolas Chuvin
Human Biology Division

Maggie Burhans, Ph.D.
Public Health Sciences Division

Brianna Traxinger
Vaccine and Infectious Disease Division

Kyle Woodward
Clinical Research Division

Julian Simon, Ph.D.
Faculty Mentor
Clinical Research Division
and Human Biology Division

Allysha Eyler
Publication Tracking
Arnold Digital Library

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