David Maloney, MD, PhD
An effective lymphodepletion (LD) strategy is critical to success with chimeric antigen receptor (CAR) T-cell therapy, but also the choice of patients and even the cells used for CAR T cell manufacturing should be made with care, said David G. Maloney, MD, PhD, at the 2018 Pan Pacific Lymphoma Conference.
Maloney, who delivered the first annual Oliver Press Memorial Lecture, gave a wide-ranging overview of key considerations for CAR T cell success, which included clinical and financial challenges ranging from distinct adverse event (AE) management to unresolved payment policies that make it risky for cancer centers to undertake treatment with these agents.
Maloney is a professor at the University of Washington and medical director of the Bezos Family Immunotherapy Clinic at the Fred Hutchinson Cancer Research Center in Seattle.
There are strong distinctions in CD4 and CD8 cell populations between patients with non-Hodgkin lymphoma and healthy donors. The role of these cells makes it important to obtain CD4 and CD8 cells and combine them in the right ratio to achieve an effective response to manufactured CAR T-cell therapy, Maloney said.1
“If you just collect the T cells and make a CAR, and don’t separate the populations, you end up with a wide range of CD4 and CD8,” he said. At Fred Hutchinson, investigators have sought to give the processed cells back to patients in a defined 1:1 ratio, which Maloney said has enabled them to improve the dose response and toxicity relationship.
In addition to cell populations, the impact of LD is critical. In an early stage study, investigators used cyclophosphamide (Cy)-based LD chemotherapy with or without fludarabine (Flu) prior to CD19-directed CAR T cell immunotherapy. The more intense the LD, which enhances the grafting of infused T cells, the higher the homeostatic cytokine levels of interleukin (IL)-7 and IL-15, which lengthens T-cell persistence. “If you do Cy/Flu, you can show a difference in the proliferation of the T cells,” and in fact it can be possible to administer a second treatment, Maloney said.
In a study of CAR T-cell therapy in patients with relapsed/refractory non-Hodgkin’s lymphoma (n = 79) by Gauthier et al presented at the 2018 ASCO Annual Meeting,2 investigators used Cy/Flu and achieved a 38% complete remission (CR) rate among patients with aggressive disease (n = 9) and an 89% CR rate among those with indolent disease (n = 48).
The same study found that CR was associated with superior progression-free survival (PFS): 57.2% of patients who achieved a CR were progression-free at the 2-year mark (95% CI, 39%-83%), whereas those with partial response (PR), stable disease, or progressive disease saw a median PFS of under 9 months. The gap extended to OS. For those achieving a CR, 78% were alive at 24 months (95% CI, 63%-97%). “If you don’t have a CR, then the outcome is quite poor,” Maloney said.
Some characteristics help predict who’s going to respond. A surprising finding by Gauthier et al was that pretreatment lactate dehydrogenase (LDH) levels in patients showed an inverse relationship to outcome. “The lower the pretreatment of LDH is, the better the response and the more likely you’re going to have a durable CR,” Maloney said.
Additionally, the more T cells proliferate, the better the response, and IL-7 and IL-18 levels also correlated with CR rates, Maloney said.
“If you put this together, you can find patients with a nearly 100% chance of long-term remission if they fit into this small subset of patients.”
Adverse Event Prevention
When it comes to cytokine release syndrome (CRS), it is important to pay attention to signs of coagulopathy. Patients can have marked transfusion requirements, and this condition can translate into hepatic and renal dysfunction, along with heart arrhythmias. At Fred Hutchinson, physicians monitor IL levels to judge whether patients are undergoing CRS, so that it can be treated successfully with tocilizumab and dexamethasone, Maloney said.
Neurotoxicity is also problematic, and at Fred Hutchinson this is treated with steroids only, unless there’s ongoing CRS, he said. The onset of CRS and neurotoxicity is very rapid following infusion, although CRS precedes neurotoxicity by several days in most cases. As CAR T cells proliferate, there’s a higher chance of having neurologic toxicity or CRS.
“There’s a direct relationship. The higher the CAR T cell proliferation, generally the higher your chances of CR. This is a balancing act—you need to be able to control the CAR T cells,” Maloney said.
He compared 2 recently approved CAR T therapies—axicabtagene ciloleucel (axi-cel, Yescarta) and tisagenlecleucel (Kymriah)—with one in development, lisocabtagene maraleucel (liso-cel; JCAR017).
Axi-cell, for diffuse large B-cell lymphoma (DLBCL), in ZUMA-1 achieved an ORR of 82% and a CR of 49% among 77 patients. “These were highly refractory patients—refractory to second or later-line therapy, and also included patients who relapsed within 12 months of autologous transplant. And the results were quite spectacular,” he said.
In a group of adult patients with relapsed/refractory DLBCL, tisagenlecleucel achieved a CR plus PR of 53% (n = 81) in the JULIET trial, with a durable ORR of 38% at 3 months and 37% at 6 months. What was a key difference for tisagenlecleucel was that it could be administered in both inpatient and outpatient settings, noted Maloney.
With liso-cel, which is not approved, cells are preselected for CD4 and CD8 and 2 populations of CAR T cells are manufactured and administered, Maloney said. The cells are tagged by a transduction marker and can be potentially eliminated by an anti-EGFR antibody if necessary. The rate of AEs has appeared milder than with the previously mentioned CAR T-cell products, Maloney said. The best CR achieved by liso-cel in DLBCL so far was 59% (n = 73).
Financial Obstacles Remain
Payment challenges abound, Maloney said. Often it is necessary to negotiate with payers on a case-by-case basis. Private payers lack clear policies. “The way it’s set up is the center pays all the money up front, and if you get reimbursed 10%, that’s your problem not the manufacturer’s.” The Centers for Medicare & Medicaid Services may bundle payments resulting in additional potential loss.
Additionally, these agents have distinct characteristics that make it impossible to generalize treatment usage and AE management. “I think we need to somehow get ourselves on the same page across all of these different drugs,” he concluded.
- Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells. Sci Transl Med. 2016;8(355):355ra116. doi: 10.1126/scitranslmed.aaf862
- Gauthier J, Hirayama AV, Hay K, et al. Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma. J Clin Oncol. 2018;36(suppl; abstr 7567). meetinglibrary.asco.org/ record/162353/abstract.