While they have made a huge difference in the lives of patients with certain blood cancers, CAR-T cells remain a cumbersome type of therapy to give, encompassing a complex process of extraction of white blood cells, shipment and manufacturing, along with potentially serious toxicities. But data presented at a conference Friday point to a potentially much simpler alternative.
South San Francisco, California-based Allogene Therapeutics and its partner, Paris-based Servier, announced the presentation of initial Phase I data on their allogeneic CAR-T therapy, ALLO-501, at the American Society of Clinical Oncology’s annual meeting, which is taking place online due to Covid-19. Whereas the two CAR-T cell therapies currently on the market – Novartis’ Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel) are bespoke therapies made from patients’ own T cells, allogeneic CAR-Ts like ALLO-501 are “off-the-shelf,” being made from donor cells.
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The trial, in patients with relapsed or refractory large B-cell lymphoma and follicular lymphoma, is also using ALLO-647, a CD52-targeting monoclonal antibody for lymphodepletion, the process of clearing the bone marrow to make space for the CAR-T cells.
As of this month, Allogene and Servier said, 22 of the 23 patients enrolled had received ALLO-501, and 19 had reached at least one month of assessment as of the data cutoff. Data presented at the meeting showed an overall response rate (ORR) of 63%, including a complete response (CR) rate of 37%. The presented data include patients who received ALLO-647 at 39mg and 90mg and ALLO-501 at doses of 40 million, 120 million and 360 million cells. The higher dose of ALLO-647 was associated with a higher CR rate of 50%, deeper lymphodepletion and delayed recovery of host T cells.
Short-term efficacy is “in the same ballpark as what we’ve seen with autologous CAR-Ts with lymphoma patients, but we don’t have durability data yet because the follow-up is still short,” lead investigator Dr. Sattva Neelapu, a hematologist at The University of Texas MD Anderson Cancer Center in Houston, said in a phone interview.
With a median follow-up of 3.8 months, nine of 12 responding patients were still responding to therapy.
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“It will take a longer follow-up to confirm that responses are durable,” said Dr. Amanda Cashen, an associate professor of medicine at Washington University in St. Louis, in a phone interview. Cashen is not an investigator in the study.
No less important than response rates and duration of response is the toxicity profile. Since Kymriah and Yescarta’s 2017 approvals, and with numerous CAR-Ts in clinical development, oncologists have become better at managing the toxicities commonly associated with them, in particular neurological toxicity and cytokine release syndrome (CRS), a kind of immune system overreaction. Still, those toxicities can be serious and potentially even fatal. But so far, notwithstanding the earliness of the data, those side effects are relatively mild to nonexistent with ALLO-501.
Seven patients experienced CRS, with only one experiencing an event rated as severe, while the other six were mild to moderate. No patients experienced neurological toxicity, which in the context of cell therapy is known as immune effector cell-associated neurotoxicity syndrome, or ICANS. And notably, nobody experienced graft-versus-hose disease, which is observed with allogeneic stem cell transplant and was feared as a potential adverse event with allogeneic CAR-Ts, but has yet to materialize in the latter.
With the data being reported at ASCO including fewer than two dozen patients, and the Phase I study still recruiting toward its goal of 54, it goes without saying that it’s too early to make any final judgment about ALLO-501. Nevertheless, an off-the-shelf CAR-T therapy with all the efficacy of autologous CAR-T, but fewer of the serious side effects and hurdles, could potentially make the latter obsolete for many patients.
“If the efficacy is comparable, it will be a direct competitor and probably will replace autologous CAR-Ts,” Neelapu said. This, he added, is because the cost of production is lower and will hopefully translate into a lower cost for the product overall. In addition to the list prices of Kymriah and Yescarta in diffuse large B-cell lymphoma of $373,000 at the time of their introduction, supportive care and other associated services can push the cost well above that, into the high six digits and beyond.
Meanwhile, ALLO-501’s off-the-shelf advantage would enable more patients eligible for CAR-T to actually receive it, Neelapu said. He added that only about one-fifth of those eligible for autologous CAR-Ts end up receiving them, in part because only a limited number of often far-flung centers – usually one or two per state – can administer them, due to the onerous infrastructure requirements. “Some of the infrastructure can be simplified with an off-the-shelf product because then it’s more like a drug.”
Moreover, he said, about 15% of patients referred to MD Anderson for CAR-T don’t get the product in the end due to insurance delays and disease progression. “So we lose about 80% before the referral and another 15%” after it, he said.
Cashen agreed.
“It’s a significant burden to use the autologous products when we have to wait for them to be manufactured, and many patients can’t wait that time or have worsening disease symptoms or have complications that arise,” she said. “It’s still early to say for sure, but it’s certainly a possibility.”
Photo: CGToolbox, Getty Images
