CAR T-cell therapy ‘quite promising’ for glioblastoma
Chimeric antigen receptor T-cell therapy may overcome some of the obstacles associated with systemic therapy for patients with glioblastoma, according to a review published in Neuro-Oncology.
Although progress with chimeric antigen receptor (CAR) T-cell therapy for solid tumors has been limited, clinical trials have demonstrated the feasibility and safety of the approach for treatment of glioblastoma.
“There is an appeal of the immune system because of the power that is unlike any other treatment approach. It is also the ultimate in personalized medicine because we are engineering each individual patient’s CAR T cells,” Donald M. O’Rourke, MD, director of the Human Brain Tumor Tissue Bank and John Templeton Jr., MD, associate professor in neurosurgery at Abramson Cancer Center and Perelman School of Medicine at University of Pennsylvania, told HemOnc Today. “There are so many appealing factors in immunotherapy, but we are truly too early in the game and we need to do more work looking at this treatment in solid tumors.”
HemOnc Today spoke with O’Rourke about the what studies of CAR T-cell therapy for glioblastoma have shown so far, the challenges that still remain, and the potential long-term viability of this treatment modality will be in this setting.
Question: What have data suggested so far about the potential of CAR T-cell therapy for glioblastoma?
Answer: We treated 10 patients in our first human study against the antigen EGFRvIII, which is different from the mutated EGFR protein in lung cancer. We identified two limitations of CAR T-cell therapy in glioblastoma — the heterogeneity of tumors and the solid tumor microenvironment. The tumor microenvironment in glioblastoma is immunosuppressive, and this becomes even more dramatic when CAR T cells are administered. This is probably an adaptive response to the CAR T cells. We need to develop strategies to overcome these limitations. In our preclinical work that utilizes both the EGFRvIII target and the IL13R2 receptor target, we engineered CAR T cells in combination with checkpoint inhibitors and found we can enhance the efficacy of CAR T cells with checkpoint inhibitors. Depending on the target used, the checkpoint pathway to be inhibited was different, so we compared a CAR T-cell population targeting EGFRvIII with PD-1 inhibition, and we received a higher level of response. Further, if we paired the IL13R2 CAR T cell with a distinctly different checkpoint inhibitor, we augmented the response to CAR T-cell therapy against IL13R2 glioblastoma cells. The choice of the checkpoint inhibitor should be different depending on the CAR T-cell population and the specific tumor target. We are now getting to the point where we will be able to identify the combinations that should be used for patients with CAR T cells in our clinical trials for glioblastoma.
Q: How may CAR T-cell therapy overcome some of the obstacles associated with systemic therapy in glioblastoma?
A: CAR T-cell therapy is a different kind of therapy. It is a living biological drug that is personalized for each patient because it uses the patient’s own T cells. The degree of specificity is greater than standard chemoradiation because specific mutations in glioblastoma cells are targeted by engineered T cells. In theory, these approaches may be better suited for tumors like glioblastoma that exhibit intratumoral heterogeneity because several distinct mutations could be specifically targeted. Immunotherapies also have the advantage that they have memory and can, in theory, get to more diffuse areas of tumor infiltration that are not amenable to surgery or radiation.
Q: What short-term and long-term viability or benefit do you anticipate CAR T-cell therapy will have for this malignancy?
A: This disease needs new therapy. It is one of the more difficult prognoses for adults with cancer. Few treatment advances have been made in the past 30 to 40 years. Most people in the field believe immunotherapy is where the most clinical gains will be made. Those of us at University of Pennsylvania are placing a lot of our emphasis in this area. The overall picture is quite promising, but we are way behind the progress made in leukemia and lymphoma.
Q: What is the next step for research?
A: Our next step is to add the CAR T cells with checkpoint inhibitors to begin to probe combinations of immune therapies. However, we have to solve many issues, including optimizing penetration of T cells into the brain, modulating the suppressive tumor microenvironment, increasing CAR T-cell longevity and efficacy, and determining which targets are best for glioblastoma.
Q: Is there anything else that you would like to mention?
A: The bottom line is that a lot more work is needed to figure out why there has been so much success with CAR T-cell therapy for blood cancers but much less success for solid cancers. We have only treated a small number of patients, and not many centers are doing this work. We need to determine approaches that will improve our understanding and jumpstart this work. – by Jennifer Southall
Bagley SJ, et al. Neuro Oncol. 2018; doi:10.1093/neuonc/noy032.
O’Rourke DM, et al. Sci Transl Med. 2017;doi:10.1126/scitranslmed.aaa0984.
For more information:
Donald M. O’Rourke, MD, can be reached at Abramson Cancer Center, 3400 Civic Center Blvd., 10th Floor Perelman Center, Philadelphia, PA 19104.
Disclosure: O’Rourke reports no relevant financial disclosures.