SAN DIEGO – Since 2016, oncologists at the Chaim Sheba Medical Center in Israel have been treating their large B-cell lymphoma patients with autologous CD19-directed CAR T-cell therapy manufactured at the facility. Now, they have the data showing that their point-of-care autologous CAR T-cell therapy has comparable efficacy, better tolerability, and a shorter wait time compared to commercially available, centrally manufactured products.
At the American Society of Hematology's annual meeting on Sunday, Ronit Marcus, an oncologist at the Sheba Medical Center, presented results from a retrospective analysis comparing the outcomes of advanced large B-cell lymphoma patients treated either with Sheba's point-of-care CAR T-cell product or with commercially available CD19-directed CAR T-cell therapies, Gilead Sciences' Yescarta (axicabtagene ciloleucel) or Novartis' Kymriah (tisagenlecleucel).
The analysis, Marcus noted, is the first that she and her colleagues knew of to compare the activity a CD19-directed CAR T-cell therapy produced and given at an academic medical facility against commercially available products that were produced elsewhere.
Since their commercial approvals, Yescarta and Kymriah have transformed the treatment landscape for lymphoma patients, Marcus noted. Both therapies netted US Food and Drug Administration approval in 2017 and European Medicines Agency approval in 2018. The treatments involve harvesting patients' immune cells, modifying them to express chimeric antigen receptors that target CD19 on the surface of B cells, then reinfusing them as a one-time treatment, and have led to durable remissions in countless patients.
But these therapies are not without their limits, Marcus said. For one, they carry six-figure price tags. The list prices for Yescarta and Kymriah are $424,000 and 475,000, respectively. Patients often must wait long periods to receive them, as the cells are frozen, shipped over long distances to central facilities, manufactured, then shipped back to the patient's treatment location. During this waiting period, which ranges from three weeks to a month for Yescarta and Kymriah, patients with particularly aggressive lymphomas often require bridging therapy to keep their cancers from spreading further.
These limitations make the prospect of manufacturing bespoke CAR T-cell therapies right at the patient's place of treatment an attractive one to oncologists and patients alike. "Not every place can [offer] commercial CAR Ts," Marcus said. "The costs are very high, … and there are very strict indications."
Comparable efficacy, improved toxicity
Of the 330 patients included in the study, 132 received Yescarta, 104 received Kymriah, and 94 received the point-of-care CAR T-cell therapy. All patients who got the point-of-care therapy did so at Sheba, and the rest of the patients were treated at one of three centers: Sheba, the Rambam Healthcare Campus in Israel, or Memorial Sloan Kettering Cancer Center. Marcus noted that although there is now another commercially available CD19-directed CAR T-cell therapy on the market in the US and Europe, Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel), that treatment still isn't available in Israel, so it was not included in the study.
Marcus and her colleagues measured a number of outcomes between the treatment arms and found that the point-of-care treatment performed comparably to Yescarta and Kymriah. The researchers used propensity score matching and statistical analysis to ensure that patients with similar characteristics were enrolled in the three arms. Even so, the patients who got the point-of-care therapy had slightly higher rates of refractory disease, Marcus noted.
Importantly, the vein-to-vein time for the point-of-care therapy was 11 days, versus 38 days for Yescarta and 44 days for Kymriah. This vein-to-vein time, which comprises the time from the moment patients' cells are harvested to when they receive the CAR T-cell infusion, is an important consideration with these therapies, especially since patients tend to have aggressive, advanced disease and can't wait for treatment for weeks on end.
"That [shorter vein-to-vein time] abrogated the need for systemic bridging therapy," Marcus said. With Yescarta and Kymriah, 72 and 70 patients, respectively, required bridging therapy while they waited for their CAR T cells. The same was true for just 19 patients who received the point-of-care CAR T cells, Marcus said. And in these cases, the bridging treatment they received was limited to steroids as opposed to systemic chemotherapy. "This rapid vein-to-vein time makes [the point-of-care option] particularly suited to patients with rapidly progressing disease," Marcus said, adding that it also meant that fewer patients dropped out of the study than with the other products, though she didn't report specific data on this point.
After a median follow-up time of 35 to 49 months, depending on the product, Marcus characterized patients' median overall survival on the three products as "comparable," though patients' median overall survival on Yescarta was the best numerically at 21 months, versus 16 months with Kymriah and 15 months with the point-of-care therapy. The median progression-free survival was 11 months with Yescarta, versus 3.3 months with Kymriah, and 3.0 months with the point-of-care therapy.
When asked to account for the superior outcomes seen with Yescarta, Marcus pointed to the baseline status of the patients treated with the point-of-care therapy. Even though the researchers employed a statistical analysis to adjust for these differences in the retrospective cohorts, she said that the patients treated at Sheba had more advanced disease and other indicators of poor health.
"These were really different populations, and there were maybe some unmeasured confounders that we didn't target [with the statistical adjustments]," she said. "We still don't have the full understanding of the differences between the groups." She also noted that the dosing for the CAR T-cell products was different. The Sheba therapy involved 1 million non-cryopreserved cells per patients' kilogram of bodyweight, whereas the commercial products involved 2 million cryopreserved cells per kilogram.
The point-of-care product had an improved safety profile compared to the commercially available cell therapies. Just 26 percent of patients treated with Sheba's product experienced grade 2 or higher cytokine release syndrome, versus 52 percent of patients treated with Yescarta and 37 percent of patients treated with Kymriah. Fourteen percent of patients who received Yescarta required admission to the ICU within one month of their infusion, whereas the same was true for 6.1 percent and 3.2 percent of patients treated with Kymriah and the point-of-care therapy, respectively.
"Sheba point-of-care CAR T is a safe and effective treatment for large B-cell lymphoma with comparable results to commercial options," Marcus concluded.
Implications, availability
Although a head-to-head comparison may suggest otherwise, Marcus said that she and her colleagues were "not trying to replace the commercial CAR Ts" with the point-of-care product. "We are just trying to [offer] a complementary option, with shorter time to infusion and lower cost, and with academic options," she said.
The regulatory path for point-of-care CAR T-cell therapies has historically been murky. Regulators approve products based on shared characteristics that can't necessarily be guaranteed across products manufactured at different sites with different capabilities. But at the Sheba Medical Center, Marcus and her colleagues are already treating patients with the point-of-care therapy outside of the clinical trial setting, with the go-ahead from Israeli authorities. The product isn't reimbursed by Israel's national healthcare system, but for patients who can't access commercially available therapies like Yescarta or Kymriah, it is another option.
"This is part of our daily use in the clinic," Marcus said. "And I hope that this [study] will be an opening for further options."