A new analysis of 2 patients who received chimeric antigen receptor (CAR) T-cells has found that CAR T cells remained detectable more than 10 years after infusion, with sustained remission in both patients. The investigation into these 2 cases is described in the journal Nature and they represent the 2 longest persistent responses of CAR-T therapy recorded to date against chronic lymphocytic leukemia (CLL).
Currently, there is little known about the long-term potential and clonal stability of infused CAR T cells. The investigators examined long-lasting CD19-redirected CAR T cells in two patients who achieved complete remission in 2010. “As CAR T cells become more effective, they have the potential to better treat a number of cancers, with a real potential to reduce mortality,” said David L. Porter, MD, who is the Director of Cell Therapy and Transplantation at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. “It is possible that at least for some patients they may be able to replace more toxic therapies, such as blood and marrow stem cell transplants, which are associated extensive morbidity and mortality.”
The investigation into these two cases showed a highly activated CD4+ population developed in both patients, and there was a stabilization of the clonal make-up of CAR T cells and the long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics. They also exhibited ongoing functional activation and proliferation.
In one patient, CD4+ cells made up 97.5% of CAR T cells at year 1, and 99.6% from year 3.4 to the latest time point (9.3 years) after infusion. In the second patient, CD4+ cells made up 97.6% of CAR T cells at 7.2 years after infusion. The CAR-T cells detected in one of the patients at year 9.3 were exclusively CD4+. This finding suggests the possibility that CD4+ T-cells may be primarily responsible for cytotoxicity against CD19-expressing cells. “Strongly up-regulated antigen mediated signaling pathways and up-regulation of GZMK, GZMA, and PRF1 supported this notion, as well as functional characterization of these cells in response to CD19 stimulation,” the authors wrote in their report.
CAR-T cells already have had a dramatic impact for patients on numerous CD19+ B cell malignancies, such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, and CLL. Dr Porter said that initially, CAR-T cells were tested only in patients with advanced relapsed and refractory disease, who had almost no effective treatment options available. “The complete response rates have varied between 35% to over 90%, with long-term remissions seen in between 30% and over 70% of patients depending on the disease. In my opinion, this represents a whole new paradigm for cancer therapy,” Dr Porter said.
CAR-T cell therapies are being investigated earlier in the course of the disease and Dr Porter stated the initial data on their use as first-line or second-line therapy in high-risk patients are very promising, particularly for ALL and non-Hodgkin lymphoma (NHL). “CAR-T cells are indeed precision medicine. Their immune cells are taken from their body, genetically modified so that they can now target and kill their own lymphoma cells, grown in the laboratory and reinfused back into their own body. This is as personalized therapy as one might imagine,” he said.
There is extensive research underway in the field of CAR-T therapies, and studies include not just B-cell malignancies, but solid tumors as well. In 2017, Kymriah® became the first CAR-T therapy approved by the United States Food and Drug Administration (FDA) for the treatment of pediatric and young adult patients with ALL, and it has since been approved for some types of lymphoma. “There is no doubt that CAR-T cells will become more potent, be applied to newer diseases, and become safer with less side effects. With newer rapidly changing improved technologies, I believe CAR-T cells will indeed be able to reduce morbidity and mortality for many patients,” Dr Porter said.
Olalekan Oluwole, MBBS, MPH, an associate professor of Medicine, Hematology and Oncology, at Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, said CAR T cell therapy has revolutionized the way patients with relapsed or refractory ALL, large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma are treated. “The FDA approved cell therapy products are a testament to this. Before the onset of CAR T cell therapy, patients with chemotherapy refractory lymphoma had little if any real options, and the majority died of the disease,” said Dr Oluwole. However, he said with just 1 CAR-T therapy, 44% of patients with large cell lymphoma are alive 4 to 5 years and beyond. “This is impressive because these patients have not needed any therapy since the 1 dose of CAR-T they received many years earlier. This suggests that they may be cured of the lymphoma.”
The quality of the CAR-T therapy is improving steadily. Michael Savona, MD, professor of Medicine, Hematology and Oncology, director of Hematology Research at Vanderbilt-Ingram Cancer Center, said off-the-shelf CAR T products are obtained from healthy donors and they may significantly advance the field. “The advantage is that they do not require collection of T-cells from patients and are also not subject to the 3 to 4 weeks manufacturing time,” he said. “These are active areas of research. There are several being developed, but none have reached the stage of FDA approval.”
Nirav Shah, MD, an Associate Professor of Medicine in the Division of Hematology/Oncology at the Medical College of Wisconsin, Milwaukee, Wisconsin, said this therapy is now a mainstay of treatment, and as more long-term data become available it may move from last-line therapy to first or second-line therapy. “It is a very exciting time to be a cancer doctor and hopefully this will help improve outcomes for patients,” he stated. “We need to decide as a country—if it moves up in the line—whether it will be covered, and so there will be pressure to bring the cost down.”
CAR-T therapy can cost anywhere from $373,000 to $475,000 based on the specific product and indication. However, it is hoped that off-the-shelf products could be less costly. “I hope that some of the groups try to make it a more affordable therapy. We don’t know that they will charge less if it is off-the-shelf,” said Dr Shah.
Melenhorst JJ, Chen GM, June CH, et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature. 2022; 602:503-509. doi:10.1038/s41586-021-04390-6