‘CAR T cells can eradicate solid tumors,’ study in advanced neuroblastoma shows
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Key takeaways:
- Nearly two-thirds of trial participants with advanced neuroblastoma responded to an experimental CAR T-cell therapy.
- Investigators reported no cases of high-grade treatment-related toxicities during the study.
A novel chimeric antigen receptor T-cell therapy induced clinically impactful antitumor responses in 63% of younger patients with relapsed or refractory, high-risk neuroblastoma, results of a phase 1/phase 2 trial showed.
The findings, published in The New England Journal of Medicine, suggest the investigational agent also has a manageable safety profile similar to other CAR T-cell therapies, researchers noted.
“Our results indicate that CAR T cells can be an effective therapeutic option, not only in patients with hematologic malignancies, but also in patients with solid tumors,” Franco Locatelli, MD, PhD, professor of pediatrics at Catholic University of the Sacred Heart and director of the department of pediatric hematology and oncology at IRCCS Ospedale Pediatrico Bambino Gesù in Rome, told Healio.
Background
Previous study has firmly established that the disialoganglioside GD2 is highly expressed on the surface of neuroblastoma tumor cells, making it an attractive therapeutic target, according to Locatelli.
A team of researchers from Italy developed a third-generation, gene edited, autologous CAR T-cell therapy (GD2-CART01) that targets GD2. The novel agent incorporates two co-stimulatory domains — CD28 and 4-1BB — with the aim of increasing its potency and efficacy, Locatelli noted.
“We also added to the construct the sequence coding for a suicide gene — or safety switch — to improve the safety profile of the approach,” he said. “Indeed, this suicide gene can be activated in case of severe or life-threatening toxicity not controlled by pharmacologic therapies.”
Methodology
Locatelli and colleagues conducted a single-center phase 1/phase 2 dose-escalation study to determine the safety, feasibility and recommended phase 2 dose of GD2-CART01 among patients aged 1 to 25 years with relapsed or refractory, high-risk neuroblastoma.
Twenty-seven patients (median age, 6.7 years; range, 2.7-18.6; 67% male) received a single infusion of GD2-CART01 at one of three dose levels (3 × 106, 6 × 106 or 10 × 106 CAR T cells/kg).
The study included 12 patients with refractory disease, 14 with relapsed disease and one who had a complete response after first-line therapy.
Researchers reported successfully manufacturing CAR T cells for all study participants.
Key findings
Investigators reported no dose-limiting toxicities during the phase 1 portion of the study. They established a recommended phase 2 dose of 10 × 106 CAR T cells/kg.
Twenty patients (74%) experienced cytokine release syndrome, with 95% of cases being either grade 1 or grade 2.
Suicide gene activation occurred for one patient using two infusions of rimiducid, resulting in “rapid elimination of circulating GD2-CART01” cells, the investigators wrote.
Infusion of GD2-CART01 cells resulted in clinical responses in 17 patients, for an overall response rate of 63% — nine complete responses and eight partial responses.
Patients who received the recommended phase 2 dose of GD2-CART01 had a 3-year OS rate of 60% and 3-year EFS rate of 36%.
Clinical implications
“We will work to increase the proportion of patients responding to GD2-CART01 and to prolong the durability of the response,” Locatelli told Healio.
Future studies are also planned to evaluate GD2-CART01 as earlier therapy for patients with neuroblastoma, according to Locatelli.
“We expect that this will translate into even better results,” he said.
Locatelli noted that the treatment development and ensuing clinical trial occurred entirely within the academic setting, without commercial support.
“This observation emphasizes that academic institutions may play a major role in the development of the most advanced and innovative therapies,” he said.
The study results suggest an overall favorable safety profile for GD2-CART01, in addition to encouraging objective response rates and durability for treatment of relapsed or refractory neuroblastoma, Oladapo O. Yeku, MD, PhD, of Mass General Cancer Center, and Dan L. Longo, MD, of Harvard Medical School, wrote in an accompanying editorial.
“As with all solid-tumor cancers, understanding the resistance mechanisms in patients who did not have a response could provide insight for the design of future clinical trials,” they wrote. “[Locatelli] and colleagues found that the tumors in patients who did not have a response retained expression of GD2, a finding that raises the question of whether immunosuppressive cytokines, myeloid-derived suppressor cells, T-regulatory cells or tumor-associated macrophages contribute to a lack of efficacy in these patients.”
References:
- Del Bufalo F, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2210859.
- Yeku OO, et al. N Engl J Med. 2023;doi:10.1056/NEJMe2300317.
For more information:
Franco Locatelli, MD, PhD, can be reached at Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Piazza Sant’Onofrio, 4, 00165 Rome, Italy; email: franco.locatelli@opbg.net.
Perspective
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Robbie Majzner, MD
There has long been skepticism about whether CAR T cells could demonstrate the same depth of responses in solid tumors as they have in hematologic malignancies. This exciting study by Locatelli and colleagues stands out as the largest series of CAR T-cell responses in a solid tumor to date.
Approximately 60% of patients experienced an objective response to GD2-directed CAR T cells, with half of those being complete responses. This work clearly and irrefutably demonstrates that CAR T cells can eradicate solid tumors in patients.
The researchers should be congratulated on their success, which builds on previous work engineering and testing GD2-directed CARs at Baylor College of Medicine and Texas Children’s Hospital starting in the 2000s. The first CAR T cell ever tested in a child was a first-generation GD2-directed CAR that demonstrated safety and some clinical efficacy, including complete responses. However, multiple additional GD2-CAR constructs and clinical trials failed to improve on this approach, until now.
The researchers’ success suggests that iterative engineering and testing of CAR constructs in small clinical trials will be key to advancing the field. It is essential to recognize the role of academic physicians and scientists in this process, as all of this work was carried out by pediatric oncologists at academic centers, often funded by grants and philanthropy.
GD2 is expressed on normal peripheral nerves, and anti-GD2 antibodies are associated with severe pain in the clinic. However, GD2-directed CAR T cells did not cause any pain or other on-target neurotoxicities in patients, even when they eradicated GD2-expressing tumors. GD2 is expressed at much higher levels on cancer compared [with] normal nerves. Therefore, CAR T cells — like other cancer drugs — demonstrate a therapeutic window, and some expression of target antigens on normal tissue may be tolerable, opening the door to engineering CARs against a host of antigens that are highly differentially expressed.
This trial has several limitations that should be noted. First, neuroblastoma is a highly heterogeneous cancer that ranges from indolent to aggressive, and results of any single-arm, single-institution trial need to be interpreted carefully. Most durable responses on the trial were seen in patients with low-burden disease, often restricted to the bone or bone marrow. These sites may be more accessible to CAR T cells than bulky tumors, hinting that current CAR designs will be most effective when patients are in a minimal residual disease state. Finally, only half of the population of patients in this trial had received anti-GD2 monoclonal antibodies, with no indication how many received combined anti-GD2 antibody and chemotherapy, considered the de facto standard of care for relapsed and refractory patients in the United States.
Despite these limitations, this is a landmark study that shows that CAR T cells are poised to eventually alter the treatment paradigm for immunologically cold tumors, which includes most pediatric cancers.
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Del Bufalo F, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2210859.
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