PHILADELPHIA — Chimeric androgen receptor T-cell therapy has a reputation as a game-changing therapy with a hefty price tag. However, as CAR T-cell therapy pioneer Carl June, MD, explained at last week’s CAR-T and the Rise of the Cellicon Valley event at the University of Pennsylvania, autologous CAR T-cell therapy is a one-and-done treatment that can be more cost-effective if given as an earlier line of therapy.
“We need curative therapies,” June, a professor in immunotherapy at University of Pennsylvania’s Perelman School of Medicine, told the audience. “Our success is paradoxical in that it has made financial toxicity an emerging issue. We need desperately to solve this problem.”
The FDA has approved two CAR T-cell therapies: axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) for adults with relapsed or refractory large B-cell lymphoma and tisagenlecleucel (Kymriah; Novartis) for adults with relapsed or refractory large B-cell lymphoma and pediatric patients with relapsed or refractory acute lymphoblastic leukemia. The price for axicabtagene ciloleucel is approximately $373,000 per treatment, and for tisagenlecleucel it is even higher, at approximately $475,000 per treatment.
June noted that all currently approved CAR T-cell therapies are autologous, meaning derived from each patient, but there is work going on to find universal or off-the-shelf CAR T cells that are derived from other sources.
“Those will likely be very different, both in the design and in how long they will last in patients,” June said. “In the long run, I think both types will eventually be FDA approved — there will be patient-specific cells that will last for a very long time, and there will be off-the-shelf cells that will be given more often in a community health care system, rather than the more complex patient-specific cells given in mostly the high-end cancer centers.”
June explained that the two currently FDA-approved CAR T-cell products are very different regarding sustainability within the body. Both of the original patients treated with tisagenlecleucel still have circulating CAR T cells in their bodies, he said.
CAR T cells can be living drugs, June observed, citing his experience in giving the first CAR T cells in humans to patients with HIV who, now 20 years later, still have CAR T cells in their circulation. “It’s the progeny of the cells that survive,” June explained.
“The pharmacology of [CAR T] is very different than standard drugs, which are metabolized and given recursively,” he said. “[CAR T] is a one-and-done approach, and its very different than standard medications. What really differentiates CAR T-cell therapy from other therapies is that it’s not just a drug that you give; it’s a process.”
From Inpatient to Outpatient Treatment
One of the major issues that arises during this process is the commonly observed toxicities resulting from the treatment, with cytokine release syndrome as a primary concern. This side-effect requires inpatient care done at major cancer centers that provide cell therapy treatments and can often double the overall cost of the treatment.
CRS occurs in patients who respond to CAR T-cell therapy, June said. The first pediatric patient treated for leukemia with tisagenlecleucel at Children’s Hospital of Philadelphia had a fever of 106℉ for 3 days. The fever did not respond to treatment with high-dose corticosteroids or a TNF-alpha blocker to stop the immune response.
The patient’s fever started to subside after a dose of tocilizumab (Actemra; Genentech) mitigated the CRS. Tests showed that 99% of the patient’s bone marrow were leukemia cells before the CAR T-cell infusion, June said. A subsequent test at the 23-day mark after infusion showed 75% of the cells in her bone marrow were CAR T cells and she had no measurable leukemia.
“That was a remarkable response,” June said.
“[CRS] severity depends both on the dose of the cells and the tumor burden patients have,” June noted. “If you treat patients with low tumor burden it could be done as an outpatient therapy. … One way to do that is as an earlier line of therapy when patients are in an earlier stage of cancer.”
University of Pennsylvania is working on several different cell therapy trials, June said, and so far, it has accumulated more than 1700 patient-years of safety data.
“With more than a thousand patients treated, we now know that these cells are inherently safe,” June asserted. “It depends what’s being targeted, but we have never had a case where the cells themselves have become transformed.”
There are variable rates of uptake globally, June noted, with most clinical trials for cell-based immunotherapies occurring in the U.S. and China and very few in Europe or elsewhere.
“There is amazing rapid development in this field after many years where it was stagnated because there was no investment,” he said. “All of this success with CAR T has led to a massive investment in cell therapy. Hundreds of companies, mostly in the U.S. and China, are developing CAR T cells.” – by Drew Amorosi
Disclosure: June reports grant support from Novartis. He also holds intellectual property licensed by the University of Pennsylvania to Novartis.