CAR Update (2013)

ImageATLANTA—A novel, experimental T-cell therapy can induce durable responses in leukemia patients who are highly refractory to standard therapy, according to data reported at the American Society of Hematology Annual Meeting. In the study (Abstract 717), presented by David Porter, MD, Director of Blood and Marrow Transplantation at the Abramson Cancer Center at the University of Pennsylvania, nine of 12 leukemia patients who received infusions of a genetically engineered therapy derived from their own T cells responded to the therapy, including five complete responses (CRs). Two patients remain in remission more than two years later. The therapy consists of reprograming the patients' T cells to target tumor cells through a gene modification technique using a HIV-derived lentivirus vector. The vector encodes an antibody-like protein, chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to the CD19 protein. Then, the new cells are infused back into the patient's body after lympho-depleting chemotherapy. Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL and ALL tumor cells, and normal B cells. All of the other cells that do not express CD19 are ignored by the modified T cells, thereby limiting the systemic side effects that are typically experienced during traditional therapies. “Our results show that CAR-modified T cells have great promise to improve the treatment of leukemia and lymphoma,” said the trial's leader, Carl June, MD, Professor of Immunotherapy and Director of Translational Research at Abramson. “It is possible that in the future, this approach may reduce or replace the need for bone marrow transplantation.”DAVID PORTER, MD: “The treatment eradicated large amounts of tumor among the responders. Bulky tumors were eradicated, and there was a massive expansion of cells—up to 10,000-fold—which was associated with tumor response.”CARL JUNE, MD: “Our results show that CAR-modified T cells have great promise to improve the treatment of leukemia and lymphoma. It is possible that in the future, this approach may reduce or replace the need for bone marrow transplantation.”Asked for his opinion, OT's Clinical Advisory Editor for Hematology/Oncology, Mikkael Sekeres, MD, said, “The use of genetically engineered T cells to treat cancer has been a holy grail of sorts in oncology for more than a decade. It is incredibly exciting that Dr. June and colleagues have demonstrated at the very least proof of principle in their research. This appears to be a heavily pretreated population of patients, who ordinarily would be refractory to further therapeutic interventions. This type of response rate is impressive, albeit in a limited number of patients.” Pave Way for Paradigm Shift Porter said the results appear to pave the way for a potential paradigm shift in the treatment of these blood cancers, which in advanced stages offer the possibility of a cure only with bone marrow transplantation. BMT, however, requires lengthy hospitalization and there is a mortality risk of at least 20 percent, and even then offers only about a 50 percent chance of cure. “New, more effective therapies for advanced, high-risk CLL are necessary,” he said. “Prognosis is predictable based on many factors, including cytogenetics, numerous biomarkers, and response to therapy. Patients with multiple relapsed or refractory disease or high-risk features have poor prognosis, and the disease is incurable except by allogeneic BMT or stem-cell transplant [SCT].” The primary objective of the pilot study was to determine the safety, feasibility, and immunogenicity of genetically modified CTL019 (formerly called CART19) cells in patients with CD19+ leukemia and lymphoma. These patients had CD19+ B cell malignancies with no available curative options, such as autologous or allogeneic SCT, he said. At least two prior therapies had failed in all the patients, who had received a median of five prior regimens. They had disease progression within two years of their last treatment, and their prognosis was limited with available therapies.” The researchers infused 10 CLL patients, median age of 66, with these cells. Lympho-depleting chemotherapy was given four to seven days before that, and patients then received a wide range of cell doses. After a median follow-up of eight months, three of the 10 CLL patients achieved a complete response lasting 28, 27, and seven months with no evidence of disease in the blood or bone marrow, Porter reported. Four CLL patients had a partial response, two of them for 4 months, one for three months, and one for two months. Two CLL patients had no response, and one CLL patient was unavailable for response. In addition, two children with ALL also achieved a CR. Two of the first three CLL patients treated with the protocol—whose cases were detailed in August 2011 in the New England Journal of Medicine (2011;365:725-733) and Science Translational Medicine (2011;3:95ra73)—remain in complete remission more than two years after their treatment, with the CTL019 cells still circulating in their bodies, he said. In the patients who experienced CR, the CTL019 cells exhibited vigorous proliferation after infusion, with the biggest expansion activity usually occurring 10 to 31 days after infusion. “Ultimately, the treatment eradicated large amounts of tumor among the responders,” Porter said. “Bulky tumors were eradicated. And there was a massive expansion of cells, up to 10,000-fold, which was associated with tumor response.” Tests of patients in complete remission also show their body's normal B cells have been eliminated along with their tumors, he added. These patients now are receiving regular gamma globulin treatments as a preventive measure, with no unusual or excessive infections seen so far. Adverse Events Porter reported that there was no significant infusional toxicity. Among the CLL patients, grade 3-4 hepatoxicity was seen in five responding patients, and grade 3 renal toxicity was seen in one patient, which was reversible. All patients who responded developed a cytokine release syndrome (CRS) at the time of T-cell expansion, manifested as high fevers, nausea, hypotension, and hypoxia. “We were able to treat the CRS with anti-cytokine therapy—tocilizumab, an anti-IL-6 antibody—steroids, and etancercept, and it was almost immediately reversed,” he said, adding that the question remains whether early treatment may abrogate this response. “We don't know the right timing of anti-cytokine therapy. Right now we wait to see significant hematologic instability. For patients with hypotension or hypoxia, we administer IL-6 therapy rapidly. Improvement is almost instantaneous—hypotension normalizes within one hour.” Sekeres noted that patients enrolled in early phase studies such as this tend to be healthier than the general population and thus able to tolerate these types of adverse events better—“The tolerability of such an activated immune response in a broader patient cohort remains to be seen.” “This approach has huge potential in hematologic malignancies, and I share the investigators' enthusiasm,” Sekeres continued. “It is difficult to speculate whether this could replace hematopoietic SCT. It likely would require significant institutional infrastructure, and/or costs, to reproduce this approach at centers outside of Penn. Nevertheless, this has great promise, and the responses seen so far are incredibly exciting. The durability of responses, and response rates in a broader patient population, remain to be seen.” In addition to Porter, other Penn researchers reported on other results from the T-cell therapy trials: Michael Kalos, PhD, Director of Translational and Correlative Studies Laboratory, gave an oral presentation (Abstract 756) explaining how the cells home to disease sites and elicit ongoing responses and long-term B cell aplasia. Stephan Grupp, MD, PhD, Director of Translational Research in the Center for Childhood Cancer Research at Children's Hospital of Philadelphia, presented a poster (Abstract 2604) that described how the researchers were able to manage the CRS with tocilizumab. In an interview, John C. Byrd, MD, Chair of Leukemia Research, Professor of Medicine and Medicinal Chemistry, and Director of the Division of Hematology at Ohio State University, said, that while the results are from only a small number of patients, the findings do demonstrate promise for controlling resistant CLL and ALL. “The results are encouraging because of the durability of the complete remissions. CRS is a significant adverse event that likely will be manageable as strategies are developed to abrogate it while hopefully not diminishing the anti-tumor effect of this treatment. “This is a very promising therapy based upon early data, but much more work needs to be done to assure safety before it can even expand to larger Phase II/III studies. The group at Penn and other investigators in the field are to be commended for their devotion to this modality of cellular therapy.” During the question-and-answer period, Porter agreed that more work needs to be done to develop a more specific antigen that will not result in B-cell aplasia—“We are interested in developing RNA CARs, which are self-limited to allow for B-cell development,” he said, also noting that the long-term impact on response of the specific CARs is still unknown. Agreement Between Penn and Novartis In August, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to further study and commercialize these novel cellular immunotherapies using CAR technologies. As part of the transaction, Novartis acquired exclusive rights to CTL019 cells from Penn. The plan is to build a joint research and development program devoted to the discovery, development, and manufacturing of adoptive T-cell immunotherapies.