Allogene Therapeutics’ gamble on a never-before-seen trial strategy seems to be paying off, with the biotech’s off-the-shelf cell therapy eradicating residual lymphoma in over half of evaluated patients in the study’s first data drop.
The small slice of data includes 24 patients out of a planned enrollment of around 220 for the phase 2 ALPHA3 trial, all of whom still had minimal residual disease (MRD) following six first-line rounds of chemotherapy. Seven of the 12 patients given Allogene’s donor-derived CAR-T therapy cema-cel tested negative for MRD at day 45, compared to two of 12 patients in the control arm.
The 41.6% difference in MRD eradication between the cema-cel and control arms exceeded the 25% to 30% benchmark that is considered clinically meaningful, Allogene said in an April 13 release.
At that same 45-day time point, cema-cel treatment reduced circulating lymphoma DNA in the blood by an average of 97.7%, compared to a 26.6% increase in the control arm, Allogene announced.
The Bay Area biotech noted that cema-cel did not result in any cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome, which are common side effects of traditional autologous CAR-Ts that use T cells engineered from the patient themself. As a result, 10 of the 12 cema-cel patients were managed entirely in outpatient centers after treatment, while the other two needed hospitalization for heart-related medical conditions unrelated to the cell therapy.
“Our goal has always been to move CAR-T from a bespoke procedure available at a limited number of centers to a scalable therapy that can reach patients more broadly,” Allogene CEO David Chang, M.D., Ph.D., said in the release. “Although still early, the ALPHA3 results show encouraging MRD clearance and a favorable safety profile.”
Allogene expects enrollment for the trial to wrap up by the end of 2027, according to the release, with many more important data drops to come. Most importantly, the biotech needs to demonstrate that destroying residual disease actually prevents relapse.
Key data on event-free survival is expected in mid-2027 and mid-2028. Should Allogene succeed, it would then file for approval, and cema-cel could ultimately become the first donor-derived CAR-T therapy to get the FDA’s blessing.
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MRD has become a hot topic in oncology, as techniques for detecting the few cancer cells that can linger in the body after treatment have rapidly approved.
“MRD itself has been a concept that’s been around for a long, long time and has been used to make clinical decisions in other heme malignancies, but it hadn’t been used effectively in lymphoma,” Allogene’s Chief Medical Officer Zachary Roberts, M.D., Ph.D., told Fierce ahead of the ALPHA3 data drop.
That started to change around 2022 and 2023, he said, when evidence emerged that a positive MRD test after treatment—even though a patient may otherwise seem to have no more lymphoma—was a strong predictor of relapse.
This prognostic power, coupled with competition from approved autologous CAR-Ts in late-line lymphoma like Kite’s Yescarta and Tecartus, Novartis’ Kymriah and Bristol Myers Suibb’s Breyanzi, prompted Allogene to make a bold play at the beginning of 2024.
The company halted its pivotal phase 2 studies, the first in the donor-derived or allogeneic CAR-T field, to launch a new trial based on the theory that cema-cel could eliminate MRD after initial chemotherapy and render the need for subsequent lines of treatment moot.
Should ALPHA3 ultimately succeed, it would change the way lymphoma is treated entirely, Roberts said. At the moment, MRD isn’t routinely tested in lymphoma patients because even if there’s a positive result, there’s not much doctors can do except observe the patient and hope the disease doesn’t come back.
The most important thing that will “propel MRD into a standard of care” is if oncologists “have something to do with a positive result,” Roberts said.
“The only clinical trial that’s being run today that is designed to answer that question is ALPHA3,” he said. And because it is available off-the-shelf, cema-cel is the perfect product for the job, Roberts claimed.
Allogene’s cema-cel data comes at a critical time for the field of allogeneic CAR-T, which has struggled to secure an FDA approval even as traditional autologous approaches rapidly improve and next-gen in vivo techniques pick up steam. The slow pace of progress has led to waning investor interest, leading some in the field to declare that allogeniec CAR-T is suffering a “nuclear winter.”
For Allogene, this morning’s initial ALPHA3 data is a sign that a thaw may be on the way. A win for cema-cel could make others who had long given up on the allo approach take another look, Roberts suggested to Fierce.
“Winter always comes before spring,” he added. “These are the first little green shoots we’re seeing.”
