The study provided proof of principle that T cells genetically modified to recognize tumor-associated antigens could induce potent antitumor efficacy and validated the application of immune cell-based therapies for cancer.
—Renier J. Brentjens, MD
In a recently published study, Memorial Sloan-Kettering Cancer Center investigators demonstrated the considerable antitumor efficacy of 19-28z chimeric antigen receptor (CAR)-modified T cells in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). The ASCO Post asked lead author Renier J. Brentjens, MD, of Memorial Sloan-Kettering Cancer Center, New York, about techniques used in the study and the implications of the results.
Generating the T Cells
How do you generate the CD19-targeted T cells used as treatment in the study?
We have generated an artificial T-cell receptor specific to the CD19 antigen expressed on the surface of most B-cell tumors, including B-cell ALL, chronic lymphocytic leukemia (CLL), and B-cell non-Hodgkin lymphoma. The gene for the receptor is cloned into a retroviral vector, a replication incompetent virus. Then, patient T cells are isolated and activated; once the T cells are proliferating, the viral vector with the 19-28z CAR gene is added to the culture to allow for transfer and expression of the gene in the T cells. The T cells are then expanded in culture to the dose needed for patient treatment. This work is done in the Memorial Sloan-Kettering Cancer Center Gene Transfer Facility, directed by Isabelle Riviere, PhD.
When the target dose of T cells is achieved, the cells, which are now able to recognize the CD19 protein on the surface of the tumor cells, are infused back into the patient.
What were the most striking findings in the study?
The rapidity with which these CAR-modified T cells eradicated even large numbers of tumor cells and the fact that we could achieve molecular remissions in all patients were both very striking findings. From a more global perspective, the study provided proof of principle that T cells genetically modified to recognize tumor-associated antigens could induce potent antitumor efficacy and validated the application of immune cell-based therapies for cancer.
There is no doubt that other therapies using adoptive cell techniques for cancer will now be tested. But our findings serve as a benchmark indicating that immune cell-based therapies warrant further serious investigation and funding, and that further preclinical and clinical studies should be done.
Can you comment on the relatively rapid resumption of normal B-cell lymphopoiesis seen in study patients?
The rapidity of normal bone marrow recovery we observed points to the targeted nature of this therapy; this is in contrast to conventional chemotherapy, wherein normal bone marrow function requires a significantly longer time to recover. Our observation with respect to normal B-cell recovery in these patients may be related to limited persistence of CAR-modified T cells targeting the CD19 antigen, and this may in part be associated with the need for high-dose lymphotoxic steroid therapy in several patients to reverse symptoms related to the observed “cytokine storms” mediated by the CAR-modified T cells. Alternatively, limited persistence of our CAR-modified CD19-targeted T cells, which nevertheless allowed for molecular remissions, may in turn avoid potential long-term infections related to persistent B-cell aplasias.
Avoiding Cytokine-mediated Toxicities
Relapse after achieving minimal residual disease–negative status was observed in one patient, possibly related to the need for high-dose lymphotoxic steroid treatment for cytokine-mediated toxicities. Are there any potential strategies for avoiding or modulating this effect?
As we point out in the article, these toxicities appear to correlate to the degree of tumor bulk at the time of modified T-cell therapy. To this end, we propose infusion of CAR- modified T cells at earlier time points following salvage chemotherapy, when tumor load is at a nadir. Future studies are needed to validate this hypothesis and assess whether earlier infusion of T cells may avoid observed cytokine-mediated toxicities.
Additional studies by the group at University of Pennsylvania further suggest that some of these toxicities may be ameliorated by infusion of an anti-interleukin-6 monoclonal antibody. This would be a potential alternative approach regarding management of cytokine-related toxicities. Again, this approach will need to be studied prospectively for further validation. Finally, the use of multiple timed modified T-cell infusions when most of the tumor bulk has been previously eradicated would be another strategy to investigate in attempting to optimally apply this technology to the clinical setting.
Is there a possibility that CAR-modified T-cell treatment alone can completely eradicate malignant clones and provide cure in B-cell ALL?
We don’t yet know the answer to the question about whether CAR-modified T-cell treatment can achieve cure, but enrollment and treatment of additional patients in the study may provide some guidance. It would be of particular interest to follow patients for whom bone marrow transplantation is not an option and observe whether a single infusion or multiple infusions of the CAR-modified T cells could achieve optimal remission or potential cure of their disease.
What are the next steps in studying CAR-modified T-cell approaches to treatment?
With regard to the CD19-targeted T-cell approach, we are expanding the current phase I trial in B-cell ALL into a phase II trial, expanding the application of this approach to patients with B-cell lymphoma, and continuing enrollment on an open clinical trial that treats patients with relapsed CLL.
With regard to other applications, the current study serves as proof of principle for the CAR-modified T-cell approach to cancer. We believe that these initial clinical outcomes validate expanding this approach to targeting other cancers. We have thus expanded our preclinical studies to include investigation of this adoptive therapy approach in lung cancer, mesothelioma, ovarian cancers, prostate cancer, and other solid tumors. We currently have an open clinical trial in prostate cancer. ■
Disclosure: Dr. Brentjens has intellectual property in chimeric antigen receptors: patent number US 7,446,190, which covers the 19-28z receptor.
As was recently reported in Science Translational Medicine, Renier J. Brentjens, MD, and colleagues at Memorial Sloan-Kettering Cancer Center, New York, found that profound molecular remission was rapidly induced in patients with relapsed B-cell acute lymphoblastic leukemia (ALL) using autologous T ...