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Cellular Therapies Begin to Make Their Mark in Solid Tumors

OncLive spoke with experts working to develop cellular therapies in solid tumors to gain insights into their current standing and future in the space.

Cellular therapies in solid tumors |  Image Credit: © freshidea - stock.adobe.com

Cellular therapies in solid tumors |

Image Credit: © freshidea - stock.adobe.com

Cellular therapies such as CAR T-cell agents and bispecific T-cell engagers (BiTEs) have had a major effect on the treatment landscape of patients with hematologic malignancies with 7 agents earning indications across subtypes of leukemia and lymphoma, as well as multiple myeloma.1 In the solid tumor realm, investigators are pushing hard to integrate this class of agents into multiple disease settings, with some notable successes already.

“T-cell–redirecting therapies, including CAR T-[cell agents], BiTEs, and trispecific [antibodies], have been at the forefront of the hematologic space,” Kevin K. Zarrabi, MD, FACP, an assistant professor at Thomas Jefferson University in Philadelphia, Pennsylvania, said in an interview with OncLive®. “As a result, there’s been a renewed interest in novel immuno-oncology approaches in solid tumors. Studies have already been fairly successful in the early-phase setting, and we’re now seeing late phase development of some T-cell–redirecting therapies in solid tumors.”

Although cellular therapies have been transformative in hematologic malignancies by offering a new option for patients with previously hard-to-treat diseases, the development of these agents for the treatment of patients with solid tumors has been comparatively slow historically. Barriers to the success of these agents in this setting have included a complex tumor microenvironment, antigen heterogeneity, and immunosuppressive mechanisms that can have a negative effect on antitumor T-cell responses.1

Kevin K. Zarrabi, MD, FACP

Kevin K. Zarrabi, MD, FACP

Safety concerns have also been raised regarding the use of these agents in solid tumors. Past safety problems have included high rates of cytokine release syndrome (CRS) and on-target, off-tumor adverse effects (AEs), Zarrabi explained.

“One of the biggest challenges in solid tumors has been target identification,” Allison Betof Warner, MD, PhD, the director of Melanoma Medical Oncology, director of Solid Tumor Cellular Therapy, and codirector of the Pigmented Lesion and Melanoma Program, as well as an associate professor in the Department of Medicine in the Division of Medical Oncology at Stanford Medicine in California, added in an interview with OncLive. “In [patients with] hematologic malignancies, almost all the malignant cells express CD19, and our CAR T-cell products can go after that specific target. If you deplete CD19-positive cells, even healthy ones, that is safe for patients over the long term. In solid tumors, we have not had these great targets that are universally expressed on the tumor and are still safe to target.”

Allison Betof Warner, MD, PhD

Allison Betof Warner, MD, PhD

However, investigators are working to find solutions to these problems by exploring new targets, working to mitigate off-target toxicity, and developing new approaches beyond traditional CAR T-cell therapies. This work has already led to multiple FDA approvals for cellular therapies in solid tumors (Table).2-4

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Multiple Cellular Therapies Earn Indications in Solid Tumors in 2024

In February 2024, the FDA granted accelerated approval to the tumor-derived autologous T-cell immunotherapy lifileucel (Amtagvi) for the treatment of patients with unresectable or metastatic melanoma who previously received a PD-1 antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor.2 The regulatory decision marked the first FDA approval of a cellular therapy for the treatment of patients with a solid tumor.5

The approval was supported by data from the phase 2 C-144-01 trial (NCT02360579) which demonstrated that the objective response rate (ORR) was 31.5% (95% CI, 21.1%-43.4%) among patients who received the agent within the recommended dosing range of 7.5 × 109 to 72 × 109 viable T cells.2 The median duration of response (DOR) was not reached (NR; 95% CI, 4.1 months to NR).

In August 2024, the FDA granted accelerated approval to afamitresgene autoleucel (afami-cel; Tecelra) for the treatment of adult patients with melanoma-associated antigen A4 (MAGE-A4)–positive unresectable or metastatic synovial sarcoma who have received prior chemotherapy.3 The indication also required patients to have HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P–positive disease.

The regulatory decision was informed by data from cohort 1 of the phase 2 SPEARHEAD-1 trial (NCT04044768). Data from SPEARHEAD-1 demonstrated that patients who received a single dose of afami-cel (n = 44) achieved an ORR by RECIST 1.1 criteria of 43.2% (95% CI, 28.4%-59.0%). The median DOR and median time to response were 6 months (95% CI, 4.6-NR) and 4.9 weeks (95% CI, 4.4-8), respectively. The percentages of patients who achieved a response lasting at least 6 and 12 months were 45.6% and 39.0%, respectively.

In May 2024, the FDA approved tarlatamab-dlle (Imdelltra) for the treatment of patients with extensive-stage small cell lung cancer (SCLC) who experienced disease progression on or after platinum-based chemotherapy.4 Tarlatamab is a DLL3-targeted BiTE.

Findings from the phase 2 DeLLphi-301 (NCT05060016), which supported the approval, showed that patients who received tarlatamab (n = 99) achieved an ORR per RECIST 1.1 criteria of 40% (95% CI, 31%-51%) and a median DOR of 9.7 months (range, 2.7-20.7+). Patients with platinum-resistant SCLC (n = 27) achieved an ORR of 52% (95% CI, 32%-71%) and those with platinum-sensitive disease (n = 42) experienced an ORR of 31% (95% CI, 18%-47%).

“2024 was a landmark year for cellular therapy in solid tumors,” Betof Warner, said. “We went from everything being experimental to having FDA-approved agents. That was a huge step forward for those patients, but it’s [also] a landmark moment for the field [which] showed that this promise that we’ve seen in hematologic malignancies can come to solid tumors as well.”

Additional Agents Advancing Through the Development Pipeline in Solid Tumors

Building upon the established efficacy in hematologic malignancies and recent approvals in solid tumors, investigators are now working to develop more cellular therapies for the treatment of patients with solid malignancies.“There is a lot of work being done in patients with solid tumors. [Although most of] the development is preliminary, with more information, in the near future we will see an expansion of CAR T-cell therapies into solid tumors,” Anna Sureda, MD, PhD, head of the Clinical Hematology Department of Institut Català d’Oncologia – Hospitalet, Barcelona in Spain, noted in an interview with OncLive.

Anna Sureda, MD, PhD

Anna Sureda, MD, PhD

During the 2025 ASCO Annual Meeting, investigators presented findings from the phase 1 TRAVERSE study (NCT04696731).6 TRAVERSE evaluated ALLO-316 for the treatment of patients with advanced clear cell renal carcinoma (ccRCC). Eligible patients experienced disease progression following PD-1 axis and VEGF-targeted therapies and had CD70-positive ccRCC. Notably, patients were heavily pretreated with a median of 4 (range, 1-11) prior lines of therapy.

“ALLO-316 is an off-the-shelf, HLA-unmatched, CD70 CAR T-cell [product],” Jad Chahoud, MD, MPH, explained in an interview with OncLive. “[The administration of] ALLO-316 consists of a fludarabine and cyclophosphamide conditioning regimen, then you get the product. The optimal dose that was selected for part b [of TRAVERSE] was 8 × 10⁷ [cells].”

Jad Chahoud, MD, MPH

Jad Chahoud, MD, MPH

Chahoud is an associate member of the Department of Genitourinary Oncology and medical director of IPOP at Moffitt Cancer Center in Tampa, Florida. He is also a coauthor of TRAVERSE.

Updated findings from TRAVERSE revealed that the confirmed ORR per RECIST 1.1 criteria among patients with a CD70 tumor proportion score of at least 50% (n = 31) was 26%. The ORR among all patients who received ALLO-316 (n = 38) was 21%. In phase 1b, 4 of 5 confirmed responders had an ongoing response at the data cutoff, with 1 reaching the 1-year mark for response post ALLO-316 treatment.

In terms of safety, the AE profile of ALLO-316 was consistent with lymphodepletion and an active CAR T-cell therapy. In all patients (n = 50) the most common any-grade treatment-emergent AEs included neutropenia (60%), decreased white blood cell counts (56%), and anemia (52%). Any-grade CRS occurred in 62% of patients, however grade 3 or higher CRS was only reported in 2%. Grade 3 of higher immune effector cell–associated neurotoxicity syndrome (ICANS) and graft-vs-host disease did not occur; 8% of patients had any-grade ICANS.

“These patients [can receive ALLO-316] and go on without any therapy,” Chahoud said. “They just need to be monitored with repeat scans. [The long-term responders] are a sign that these CARs do a good, long-lasting job.”

In the prostate cancer space, the STEAP1-targeted BiTE xaluritamig (AMG 509) has displayed efficacy for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).7 Data from a phase 1 study (NCT04221542) presented during the 2024 ESMO Congress revealed that the confirmed ORR in the dose expansion cohort (n = 95) was 20.3%, including a 1.4% complete response rate. Additionally, the rate of reduced prostate-specific antigen by at least 50% (PSA50) was 49.5% and the PSA90 rate was 28.4%. During ASCO 2025, investigators presented the design of the phase 3 XALute study (NCT06691984) that will evaluate xaluritamig vs cabazitaxel or second androgen receptor–directed therapy in patients with mCRPC.8

Moreover, the Claudin18.2 (CLDN18.2)–specific CAR T-cell agent satricabtagene autoleucel (satri-cel; CT041) has demonstrated activity in patients with pretreated advanced gastric or gastroesophageal junction (GEJ) cancer.9 The agent was examined in a phase 2 study (NCT04581473) that enrolled patients with gastric or GEJ cancer who experienced disease progression following at least 2 prior therapies and had a CLDN18.2 expression of 2+ or 3+ per immunohistochemistry with a minimum tumor cell positivity of 40%.

Primary results from the trial showed that patients who received satri-cel (n = 104) achieved a median progression-free survival (PFS) of 3.25 months (95% CI, 2.86-4.53) compared with 1.77 months (95% CI, 1.61-2.04) among those who received physician’s choice of therapy (n = 52; HR, 0.366; 95% CI, 0.241-0.557; P < .0001). The 6-month PFS rates were 24% and 18%, respectively. Treatment with satri-cel also conferred a clinically meaningful overall survival (OS) benefit vs physician’s choice of therapy (HR, 0.693; 95% CI, 0.457-1.051; P = .0416). The median OS values were 7.92 months (95% CI, 5.78-10.02) and 5.49 months (95% CI, 3.94-6.93), resepectively.

“The [potential] clinical [effect] of these drugs [could be] tremendous,” Zarrabi said. “As we replicate the success we have seen in hematologic malignancies, it is foreseeable that T-cell–redirecting therapies, whether it’s BiTEs or CAR T-cell agents, could one day be in the frontline setting of many solid tumors. One of the most exciting parts of these drugs is the potential for durability of response, meaning that patients can hopefully be treated [and have good] quality of life.”

References

  1. Reinhorn D, Tak WS, Haanen JBAG, D’Angelo SP, Fashoyin-Aje LA. Autologous T-cell therapies in solid tumor malignancies: current landscape and future opportunities. Am Soc Clin Oncol Educ Book. 2025;45(3):e473440. doi:10.1200/EDBK-25-473440
  2. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed July 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
  3. FDA grants accelerated approval to afamitresgene autoleucel for unresectable or metastatic synovial sarcoma. FDA. August 2, 2024. Accessed July 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-afamitresgene-autoleucel-unresectable-or-metastatic-synovial-sarcoma
  4. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed July 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
  5. Julve M, Lythgoe MP, Larkin J, Furness AJS. Lifileucel: the first cellular therapy approved for solid tumours. Trends Cancer. 2024;10(6):475-477. doi:10.1016/j.trecan.2024.04.003
  6. Srour SA, Chahdoud J, Drakaki A, et al. ALLO-316 in advanced clear cell renal cell carcinoma (ccRCC): updated results from the phase 1 TRAVERSE study. J Clin Oncol. 2025;43(suppl 16):4508. doi:10.1200/JCO.2025.43.16_suppl.4508
  7. Kelly WK, Appleman LJ, Lin CC, et al. Xaluritamig, a STEAP1 x CD3 XmAb 2+1 immune therapy, in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): initial results from dose expansion cohorts in a phase I study. Ann Oncol. 2024;35(suppl 2):S963-S964. doi:10.1016/j.annonc.2024.08.1679
  8. Kelly WK, Morris MJ, Horvath L, et al. Trial in progress (XALute): phase 3 study of xaluritamig vs investigator’s choice of cabazitaxel or second androgen receptor directed therapy (ARDT) in post-taxane metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43(suppl 16):TPS5118. doi:10.1200/JCO.2025.43.16_suppl.TPS5118
  9. Qi C, Liu C, Peng Z, et al. Claudin18.2-specific CAR T cells (satri-cel) versus treatment of physician’s choice (TPC) for previously treated advanced gastric or gastroesophageal junction cancer (G/GEJC): primary results from a randomized, open-label, phase II trial (CT041-ST-01). J Clin Oncol. 2025;43(suppl 16):4003. doi:10.1200/JCO.2025.43.16_suppl.4003

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