NEW ORLEANS—Two clinical trials evaluating the use of genetically modified immune system T cells as cancer therapy represent important advances in the understanding of gene therapy for treatment of advanced blood-borne cancers, according to reports here at the American Society of Hematology Annual Meeting.
“Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” said the lead author of both studies, James Kochenderfer, MD, Assistant Clinical Investigator in the Experimental Transplantation and Immunology Branch of the National Cancer Institute.
“We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options. Our results are particularly exciting because they show that small numbers of these modified T cells can cause regression of highly treatment-resistant B-cell malignancies after transplant without causing graft-versus-host disease [GVHD], indicating a possible new treatment approach for those patients with limited options for their aggressive disease.”
Kochenderfer presented the results of both studies, which were performed in close collaboration with Steven A. Rosenberg, MD, PhD, Chief of the NCI's Surgery Branch.
Clinical evidence has demonstrated that a patient's peripheral blood T cells, which have been engineered with T cell receptors and chimeric antigen receptors (CARs) that recognize tumor specific molecules, can traffic directly to the tumor, become activated upon engagement with the tumor antigen, and selectively eradicate tumors, Kochenderfer explained.
Clinical studies performed at the NCI using these types of engineered peripheral blood T cells have shown significant and durable objective clinical responses in cancer patients with advanced metastatic disease, including those with refractory melanoma, sarcoma, lymphoma, and leukemia.
These encouraging results, he said in an interview, highlight engineered autologous T cell therapy as an emerging therapeutic modality that could provide new personalized targeted therapy options for cancer patients, spanning the spectrum of disease from early stages to the salvage setting.
“In lymphoma, these patients are refractory to second-line chemotherapy. This T cell therapy is critically important as salvage therapy,” he said.
JAMES KOCHENDERFER, ...Image Tools
In the first study (Abstract 168), 15 adult patients had their T cells removed, were treated with chemotherapy, and then were given an infusion of their own T cells, which had been genetically modified in the lab. The first report of the success of this type of therapy in lymphomas came in 2010 by Kochenderfer and Rosenberg in a patient whose disease has remained progression-free for more than 42 months after treatment.
The team has now demonstrated that this same approach is effective in patients with diffuse large B-cell lymphoma. This is the first report of successful treatment with anti-CD19 CAR-expressing T cells in patients with chemotherapy-refractory primary mediastinal B-cell lymphoma and diffuse large B-cell lymphoma, Kochenderfer noted.
All 15 patients had advanced B-cell malignancies. Eight patients had large B-cell lymphomas and the others had varying types of lymphoma or leukemia. They received an infusion of their own genetically modified T cells following a chemotherapy conditioning regimen of cyclophosphamide at a total dose of 60 to 120 mg/kg and fludarabine at 25 mg/m2 daily for five doses. No interleukin-2 was administered.
“The anti-CD 19 CAR T cell production takes only 10 days,” Kochenderfer said. “Before, it took 24 days, so we can treat patients faster. The goal is to deplete endogenous lymphocytes. This is essential.”
Of the 13 patients evaluable for response, seven had a complete response, five had a partial response, and one patient had stable disease. “Three of 4 chronic lymphocytic leukemia [CLL] patients have been in complete remission for more than one year. All of them had had a large number of prior treatments,” Kochenderfer reported.
“This approach offers an option for patients with chemotherapy-resistant large B-cell cancer who are not good candidates for other forms of stem cell transplantation. We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options. This approach offers an option for patients with chemotherapy-refractory large B-cell lymphomas who are not generally thought to be good candidates for hematopoietic stem cell transplantation.”
He cautioned that the approach is still an early-stage experimental therapy, and that the researchers plan to continue to further improve the protocol and evaluate it in additional patients with treatment-resistant disease.
At his oral presentation, Kochenderfer noted that acute toxicities, such as fever, low blood pressure, focal neurologic deficits, and delirium, are resolved in less than three weeks. The development of toxicity correlates with increases in cytokine levels, and then patients recover within a few days. Neurological toxicity, including delirium and aphasia, is transient.
“Most of the toxicity comes from cytokine release from the cells. We see a trend toward toxicity among responders,” he said.
The CAR CD 19 technology is being co-developed with Kite Pharma Inc. under a cooperative research and development agreement with the NCI's Surgery Branch.
The moderator of a news conference on promising precision medicine approaches for hard-to-treat blood disorders, Laurence Cooper, MD, Professor of Pediatrics at the University of Texas MD Anderson Cancer Center, said in an interview, “These patients are mortally wounded. They are all going to die without treatment. T cell therapy should be reserved for these patients.”
Post-allotransplant T Cell Therapy
Kochenderfer noted that progressive malignancy is a leading cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation. To improve treatment of B-cell malignancies that persist despite allotransplant, he and his colleagues used genetically modified T cells to treat B-cell cancers, such as leukemia and lymphoma, which did not fully respond to transplantation of stem cells from a donor (Abstract 151).
The study enrolled 10 patients who received no treatment except one infusion of genetically modified T cells that were obtained from related or unrelated stem cell transplant donors. Four patients were recipients of human-leukocyte-antigen (HLA)-matched unrelated donor transplants and six underwent HLA-matched sibling transplants.
“The patients did not receive chemotherapy or other anti-malignancy therapy with the CAR-T-cell infusions, so the responses observed in these patients are not confounded by the effects of chemotherapy,” Kochenderfer explained. “In contrast to other reports of successful treatment of B-cell malignancies with anti-CD19-CAR T cells, the patients on this study were not lymphocyte-depleted at the time of the CAR-T-cell infusions.”
Three of 10 patients experienced significant disease regression. Two CLL patients who were refractory to standard allogeneic donor lymphocyte infusions had regressions of large malignant lymph node masses after infusion of allogeneic anti-CD19-CAR T cells. “One of these CLL patients obtained a complete remission that is ongoing nine months after treatment with allogeneic anti-CD19-CAR T cells. This patient also had complete eradication of blood B cells within nine days after her CAR-T-cell infusion,” Kochenderfer said.
In another patient, CLL dramatically regressed in the lymph nodes, bone marrow, and blood within two weeks of his anti-CD19-CAR-T-cell infusion. Another patient who had mantle cell lymphoma had a partial remission that is ongoing three months after infusion of anti-CD19-CAR T cells. A fourth patient, with diffuse large B-cell lymphoma, has ongoing stable disease 11 months after infusion of anti-CD19-CAR T cells.
The other six treated patients all had short periods of stable malignancy or progressive disease after their CAR-T-cell infusions, Kochenderfer continued. Specific eradication of blood B cells occurred after infusion of CAR T cells in three of four patients with measurable blood B cells pretreatment.
Significantly, he said, none of the patients experienced GVHD, despite the fact that six of 10 treated patients had experienced GVHD at earlier time-points after their most recent allotransplant, Kochenderfer said. The most prominent toxicities were fever and low blood pressure, which resolved within two weeks.
At his oral presentation, Kochenderfer said: “We detected cells containing the anti-CD19-CAR gene in the blood of eight of 10 patients. These results show for the first time that small numbers of donor-derived allogeneic anti-CD19-CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after allotransplant without causing GVHD. Malignancies that were resistant to standard donor lymphocyte infusions regressed after anti-CD19-CAR-T-cell infusions.”
He added: “We continue to evaluate ways to enhance the persistence of these T cells in the body while reducing toxicities to improve the overall efficacy of the treatment. Infusion of allogeneic T cells genetically modified to recognize malignancy-associated antigens is a promising approach for treating residual malignancy after allotransplant.”
The results to date have sparked interest in evaluating the technique in a variety of hematologic malignancies and in some solid tumors, he said.
Asked for his opinion, Jeffrey Miller, MD, Deputy Director of the Masonic Cancer Center and the Clinical and Translational Sciences Institute at the University of Minnesota, said, “This is exciting evidence that we can overcome the barriers to stem cell transplantation and improve long-term survival outcomes. The new NCI research extends the limits of transplantation and is driving the field forward.”
The take-home message for oncologists, Miller said, is that “transduced T cells can get rid of pounds of tumor. This is practice-changing.” He added that scientists have worked out the specific proof of concept on how to use these complicated genetic models of therapies—“Now we need to know what is the best construct and setting to use these genetically modified cells.”
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