Novel technique may provide ‘incredible’ benefit to CAR T-cell therapy
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Key takeaways:
- The CAR-Enhancer technique enhanced CAR T-cell functionality and persistence in laboratory cultures and animal models.
- Researchers hope to conduct a phase 1 trial of patients with multiple myeloma.
A novel therapeutic approach may improve the persistence and functionality of chimeric antigen receptor T cells, helping to prevent relapse.
The CAR-Enhancer (CAR-E) technique also could help CAR T cells retain memory of cancer cells, allowing them to attack again if cancer does recur.
Researchers plan to conduct a phase 1 trial to evaluate CAR-E for patients with multiple myeloma, with the goal of building off the promise demonstrated so far in laboratory cultures and extensive animal models.
“The results were beyond our expectations,” Mohammad Rashidian, PhD, researcher at Dana-Farber Cancer Institute and assistant professor of radiology at Harvard Medical School, told Healio. “I’m very hopeful that this will save people’s lives.”
Background
The FDA has approved six CAR T-cell therapies for treatment of hematologic cancers.
Two of those CAR-Ts target B-cell maturation antigen (BCMA) in multiple myeloma, and about 80% of patients respond to these treatments. However, response rarely persists.
For example, half of individuals who receive idecabtagene vicleucel (Abecma; Bristol Myers Squibb, 2seventy bio) relapse within a year, and “almost everyone” relapses within 2 to 3 years, Rashidian said.
“These CAR T cells lose their functionality and don’t form proper memory,” Rashidian said. “They kill 99.9% of cancer cells, they don’t see anything else, and they don’t get any more stimulation because they get their stimulation from killing cancer cells. They start going away.”
‘Robust’ and ‘incredible’
Several research teams have attempted to engineer CAR T cells to address this challenge.
Rashidian and colleagues explored a different approach that they hope can work regardless of cancer type.
The platform delivers a fused molecule with two components — a weakened form of interleukin-2 plus the antigen to which the CAR is designed to bind.
Researchers tested the approach on BCMA CAR T cells used to treat multiple myeloma. They attached the BCMA protein to a low-affinity “almost dead” IL-2, Rashidian said. The BCMA antigen will bind to CAR T-cells, and then the low-affinity IL-2 “taps on the CAR T cell’s IL-2 receptor” due to proximity to keep signaling it, he added.
Investigators saw “robust” proliferation of CAR T cells, Rashidian said.
“We were thinking it would result in a modest enhancement,” Rashidian said. “Sometimes you get a 50% better response, but what we saw was night and day.”
This may allow patients to be treated with far fewer CAR T cells than they receive under current protocols.
“In most cases, patients get hundreds of millions of CAR T cells. We think we can lower that and inject maybe a couple million,” Rashidian said. “Patients can get CAR T cells much faster with much lower infrastructure. You can just expand CAR T cells in vivo in patients. We can adjust the level of proliferation that we want with the dosing of CAR-E and the schedule.”
The CAR-E product — which would be off the shelf, similar to other protein therapeutics — delivered “incredible enhancements” in memory formation, Rashidian added.
“Those memory CAR T cells can re-expand and not allow the tumor relapse to take over,” Rashidian said.
If patients do relapse, additional doses of CAR-E — even months after initial CAR-T infusion — can restimulate CAR T cells, findings in mouse models showed.
“The tumor antigen that is growing in some distant organ — let’s say in the liver — may not be enough to provide sufficient stimulation for memory CAR T cells residing in the spleen to expand,” Rashidian said. “The CAR-Enhancer will go everywhere. It will find those good-quality memory T cells residing somewhere tumors are not, and help them re-expand and come back into circulation.”
Rashidian and colleagues formulated two hypotheses as to the technique’s effectiveness.
“One is that this BCMA binds to CAR T cells and anchors this low-affinity IL-2, which then taps on the receptor and signals,” he said. “The second hypothesis is that this causes both the CAR and IL-2 to signal — it’s signaling from both sides. Some synergistic effect is causing this substantial transcriptomic change and this very long-lasting impact.”
Phase 1 trial
Once they secure funding, researchers plan to conduct a phase 1 trial for patients with multiple myeloma who have received BCMA-directed CAR T-cell therapy.
The dose escalation trial would evaluate and determine safety and efficacy.
The protein itself should not cause adverse events, Rashidian said.
“Patients with this type of multiple myeloma already have high levels of circulating BCMA and, though the IL-2 is toxic, its low affinity is expected to limit most IL-2-related toxicities,” he said.
The protein also has a short half-life, decreasing 50% in a few hours and clearing almost entirely within a day, Rashidian said.
Adverse events likely would stem from the enhancer’s impact on CAR T cells, and proliferation could lead to cytokine release syndrome and neurotoxicity.
“If we can do a good clinical trial, show that it’s safe and we can adjust the dose and schedule, the impact could be very strong,” Rashidian said. “I would expect that this will result in full tumor clearance. That’s what I hope.”
If the trial proves successful, the approach could be used with other CAR-T products, Rashidian said.
“As long as we can target the CAR, then we think it will work,” he said.
For more information:
Mohammad Rashidian, PhD, can be reached at mohammad_rashidian@dfci.harvard.edu.
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