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Will CAR T cells become first-line therapy for hematologic malignancies?
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Yes.
CAR T cells have already changed the treatment paradigm for recurrent and resistant DLBCL, which, as shown in the SCHOLAR-I study, has a dismal prognosis with conventional therapy, with a response rate of 26%, a 7% rate of complete response and median survival of just over 6 months. In contrast, three studies with CAR T cells have shown response rates of 59% to 88%, with about half of patients achieving a complete response and an estimated 40% of patients disease-free and possibly cured at 1 to 2 years after treatment. Even though the latter results are probably slightly inflated because the response and survival data were based on patients who received the product as opposed to the intent-to-treat population, the results appear much better than with conventional treatment. Although the often-described toxicity was considerable, it was generally limited to the month after treatment. Further, mortality was low, and morbidity was considerably less than after allogeneic transplant, a strategy often considered in this patient population.
Similar to other therapies that show excellent activity in the second- or third-line setting, there is considerable interest in moving CAR T-cell therapy earlier in the course of treatment. The ZUMA-7 trial will randomly assign patients with DLBCL in first recurrence to initial CAR T-cell therapy vs. the standard arm of salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant in responding patients. As the latter group has a 40% to 50% cure rate, the cure rate for CAR T cells will have to be significantly better than the published results to justify the cost. Alternatively, it is possible that this study may confirm the current practice of employing CAR T-cell therapy in patients who do not achieve a good partial response with salvage therapy while continuing to give high-dose therapy to patients who have a good response.
With respect to CAR T-cell therapy as initial treatment, there are several additional features apart from cost that will need to be considered. As many patients are quite ill at the time of diagnosis, the current manufacture time of 3 or more weeks may not be practical and, as the severity of CRS seems to parallel the amount of disease, CRS may be too severe, particularly in patients with comorbidities. In addition, it is possible that less heavily pretreated patients with more intact immune systems may have more severe CRS.
Finally, as many patients may not achieve complete response or relapse from complete response with CAR T-cell therapy, will such patients receive a second or third course of treatment, and at what cost? Although we know CAR T-cell therapy can salvage patients who have been heavily treated with chemotherapy, little is known about treatment in patients who have relapsed after CAR T-cell therapy.
Reference:
Crump M, et al. Blood. 2017;doi:10.1182/blood-2017-03-769620.
Dennis Cooper, MD, is chief of blood and marrow transplantation at Rutgers Cancer Institute of New Jersey and an attending physician at Robert Wood Johnson University Hospital New Brunswick, an RWJBarnabas Health facility. He can be reached at 195 Little Albany St., New Brunswick, NJ, 08901. Disclosure: Cooper reports no relevant financial disclosures.
No.
The current application of CAR T-cell therapy in hematologic malignancies is in the second- or third-line treatment setting or for malignancies that are refractory to combination chemoimmunotherapy. CAR T-cell therapy has shown promising efficacy in these settings, leading to the commercial availability of CAR T cells in non-Hodgkin lymphoma and ALL.
Multiple studies of CAR T-cell therapy are ongoing in Hodgkin lymphoma, other types of leukemia — including AML and CLL — and multiple myeloma. CAR T-cell therapy technology is rapidly evolving to create more efficacious, persistent, specific and less toxic cells.
Currently, CAR T-cell therapy is not used frontline due to several limitations. These limitations include the time it takes to manufacture individualized CAR T-cell products specific to the patient, the limited availability of the technology used to manufacture this product, the high cost of the manufacturing process, and the potential for high toxicity. At this time, CAR T-cell therapy can only be administered at experienced institutions within highly specialized programs by providers experienced in cellular and immunotherapy. A multidisciplinary approach is required to manage the potential toxicities of CAR T-cell therapy.
In order to become a first-line therapy in hematologic malignancies, similar to standard chemoimmunotherapy regimens, these issues must be addressed. Already, many of these areas are being improved. There are new devices and manufacturing systems being developed to shorten the manufacturing time and production cost of CAR T cells. Preclinical data from new CAR T-cell constructs show promising improvements in the tumor-killing ability of these cells as well as a reduction in potential toxicities. More studies in the frontline setting and wider availability could make the possibility of CAR T-cell therapies as a primary therapy for hematologic malignancies a reality in the future.
Monalisa Ghosh, MD, is assistant professor of internal medicine and bone marrow transplant and cellular therapy specialist at University of Michigan Rogel Cancer Center. She can be reached at 1540 E. Hospital Drive, SPC 4257, Ann Arbor, MI, 48109-4257. Disclosure: Ghosh reports no relevant financial disclosures.