NEW YORK – In the autologous cancer cell therapy space, 2024 brought a long-awaited first: regulatory approvals in solid tumor indications.
The approvals proved that these bespoke therapies are effective in settings beyond blood cancers. They also signaled that, as far as cell therapies go, chimeric antigen receptor (CAR) T-cell therapies aren't the only autologous treatments that can generate deep and durable responses.
In fact, seven years after autologous CAR T-cell therapies first came to market, the US Food and Drug Administration approved a tumor infiltrating lymphocyte (TIL) therapy and a T-cell receptor (TCR) T-cell therapy.
Amtagvi leads the way
In February, the FDA approved Iovance Biotherapeutics' autologous TIL therapy Amtagvi (lifileucel) for advanced, previously treated melanoma patients. It was the first time the regulator had approved any autologous cell therapy for a solid cancer, and it came after years of filing delays and regulatory hurdles.
The treatment is complex and patient specific. It involves surgically resecting a patient's tumor, harvesting and expanding TILs from it ex vivo, and then reinfusing the TILs as a one-time treatment together with high-dose interleukin-2, following lymphodepleting chemotherapy. Learning to administer such a treatment in the commercial setting was a big part of what defined 2024, said Daniel Olson, an oncologist at UChicago Medicine who treats patients with melanoma and sarcomas.
"The huge takeaway from the lifileucel launch is that we actually can get these therapies into the clinic and use them in a meaningful way," he said. "This is a complicated treatment, but it's certainly something that can be done."
Oncologists, including Olson, have already begun to notice the galvanizing effect of Amtagvi's approval on the cell therapy field. "This is a sentinel approval that will hopefully be followed by many other therapies," he said. "It's a huge event."
Tecelra comes second
Six months after Amtagvi broke ground as the first autologous cell therapy approved in a solid tumor indication, the FDA approved Adaptimmune's Tecelra (afamitresgene autoleucel) for biomarker-defined patients with synovial sarcoma, marking the second solid tumor cell therapy to enter the commercial market. The autologous TCR T-cell therapy is indicated for patients with MAGE-A4-expressing synovial sarcoma who test positive for the human leukocyte antigen types HLA A*02:01P, HLA A*02:02P, HLA A*02:03P, or HLA A*02:06P.
Tecelra involves harvesting patients' immune cells, engineering them to target the major histocompatibility complex (MHC) peptide MAGE-A4 on the surface of sarcoma cells, and then reinfusing them after patients receive lymphodepleting chemotherapy.
"The most exciting part about 2024 is that we now have cell therapies other than CARs achieving FDA approval," said Stephen Gottschalk, the chair of the department of bone marrow transplantation and cellular therapy at St. Jude Children's Research Hospital. "The efficacy of cell therapies in the solid tumor space has been limited, but these two regulatory approvals should at least dampen some of the criticism and skepticism that we will not be able to generate efficacious cell therapy products for this group of cancers."
Though both Amtagvi and Tecelra have made a splash in the cell therapy field, oncologists emphasize that neither treatment is a true cure, and that more can be done to improve their efficacy. Despite being approved, both therapies remain out of reach for many patients due to their cost and availability only at specialized centers. Amtagvi and Tecelra have list prices of $515,000 and $727,000, respectively. Additionally, Tecelra's HLA-restricted label keeps the treatment off-limits to many patients without White, European ancestry.
Improving existing therapies
Beyond the solid tumor space, 2024 also brought new approvals for CD19- and B-cell maturation antigen (BCMA)-directed autologous CAR T-cell therapies, including one that entered the market for the first time: Autolus Therapeutics' CD19-directed autologous CAR T-cell therapy Aucatzyl (obecabtagene autoleucel) as a treatment for relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).
The treatment is a CD19-directed autologous cell therapy, like Novartis' Kymriah (tisagenlecleucel), Gilead Sciences' Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel), and Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel). However, unlike these established therapies, two of which have been on the market since 2017, Aucatzyl has what Autolus has called a "fast off-rate," which improves the therapy's persistence and tolerability. The treatment, which can be split into two doses instead of a one-time infusion, is approved for use in the outpatient setting, in part thanks to its improved safety profile.
In multiple myeloma, Gilead subsidiary Kite and partner Arcellx showcased new data on what also looks to be a better safety profile for their investigational BCMA-targeted autologous CAR T-cell therapy, anitocabtagene autoleucel (anito-cel), compared to already approved myeloma cell therapies. At the American Society of Hematology's annual meeting earlier this month, Kite and Arcellx shared early Phase II data from the registration-directed iMMagine-1 clinical trial, in which the overall response rate on anito-cel was 97 percent, and only one patient experienced cytokine release syndrome above grade 3.
Based on cross-trial comparisons, however imperfect, anito-cel's efficacy does not initially look much better than available BCMA-directed multiple myeloma CAR T-cell therapies, BMS's Abecma (idecabtagene vicleucel) and Johnson & Johnson's Carvykti (ciltacabtagene autoleucel). However, its safety profile does. "The most encouraging [thing] was ... less neurotoxicity," said Michael Rosenzweig, a hematologist and oncologist at the City of Hope Medical Center. "I'm particularly pleased with the lack of delayed neurotoxicity in the study, as this is a major concern with Carvykti."
Oncologists like Rosenzweig are optimistic that the better safety profile is just the beginning of the improvements seen with next-generation cell therapies. The iMMagine-1 trial, he hopes, will show that "future products will only improve on what is available today and that we have not yet reached our maximum capabilities to improve treatment for relapsed multiple myeloma."
Kite and Arcellx are already conducting a Phase III trial of anito-cel, dubbed iMMagine-3, in which the firms are pitting their product against standard treatment in advanced multiple myeloma patients who've received between one and three prior lines of treatment.
Longer-term toxicities raise concern, FDA scrutiny
Though 2024 brought encouraging news for new autologous cell therapies, the year also brought heavier scrutiny for more established CAR T-cell therapies, including Novartis' Kymriah, Gilead's Yescarta and Tecartus, BMS's Abecma and Breyanzi, and J&J's Carvykti.
Earlier this year, the FDA announced that it was requiring the manufacturers of these treatments to update their labels with boxed warnings about the risk of second primary T-cell cancers. The warning requirement was based on an FDA analysis of post-marketing data and clinical trial reports showing that some patients treated with these therapies went on to develop T-cell malignancies, including CAR-positive tumors. "This raised understandable concern among patients who are eligible for these therapies and among providers who administer them," said May Daher, an assistant professor of stem cell transplantation at MD Anderson Cancer Center.
Some oncologists pushed back against FDA's actions by questioning whether the observed cases of secondary T-cell malignancies are truly linked to the CAR T-cell products themselves. "The biggest question is whether these malignancies are really caused by the CAR, or whether it's just a reflection on the fact that a lot of CAR therapies are [given] in the recurrent and refractory cancer setting, where patients have received a lot of cytotoxic agents," Gottschalk said, adding that these other cytotoxic agents could have caused mutations in the oncogenes that led to the T-cell malignancies.
Following FDA's requirement for the boxed warning, several research groups began investigating whether there was a causal link between CAR T-cell therapies and the risk of a secondary T-cell malignancy, and in one meta-analysis published this fall, researchers found that the risk of secondary malignancies were similar in patients who had gotten CAR T-cell therapies and those treated with standard treatments.
"More work is needed to dissect the respective contributions of CAR therapy versus other confounding factors, but so far, no causality has been established, and the risk seems to be very low," Daher said. To better understand these risks, she said it's important that patients receiving CAR T-cell therapies receive lifelong monitoring for any late toxicities and second malignancies.
Expanding indications
Even as regulators questioned the safety of CAR T-cell therapies, they approved marketed products, particularly BMS's Breyanzi, in new indications. Over the course of 2024, Breyanzi netted FDA approvals in myriad new settings, including relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma after at least two lines of therapy; relapsed or refractory follicular lymphoma after two or more lines of therapy; and relapsed or refractory mantle cell lymphoma after at least two prior lines of systemic therapy.
BMS also scored an additional indication for Abecma, which it codevelops with 2seventy bio, in relapsed or refractory multiple myeloma after two or more lines of treatment, and J&J garnered another approval for Carvykti, which it codevelops with Legend Biotech, in relapsed or refractory multiple myeloma after at least one prior line of therapy.
In line with multiple myeloma cell therapies' movement toward earlier-line indications, the FDA's Oncologic Drugs Advisory Committee (ODAC) in April unanimously voted in favor of using minimal residual disease (MRD) as a clinical trial endpoint that can facilitate accelerated approval of multiple myeloma drugs.
Looking to 2025
In 2024, the FDA approved nine new and expanded indications of autologous cell therapies compared to none in 2023. Industry observers believe 2025 could be another busy year of approvals in this burgeoning field.
New classes of therapies are in clinical development, including in solid tumor indications, and new entrants in established therapy classes may shake up the status quo. MD Anderson's Daher is particularly interested in forthcoming readouts of engineered natural killer cell therapies, including in areas outside oncology such as autoimmune diseases. Gottschalk is keeping an eye on GD2-directed CAR T-cell therapies in pediatric brain cancer patients, and Olson is looking forward to data on engineered, selected, and IL-5-bound TIL therapies in solid tumors.
Further down the line, oncologists anticipate increased interest in in vivo CAR T-cell therapies, which would involve administering a gene directly into patients' T cells without harvesting them first. Although those treatments are mostly still in the preclinical stages, Gottschalk sees a lot of excitement over the idea. "It's a little bit too early to say [but] this whole idea of in vivo gene delivery could potentially make these therapies more affordable and more accessible," he said.