Top advances of the year in autologous cellular therapy in melanoma and solid tumors

Abstract

The year 2025 marked significant advances in autologous cellular therapy for melanoma and solid tumors, building on landmark regulatory approvals in 2024. Lifileucel, the first Food and Drug Administration‐approved tumor‐infiltrating lymphocyte (TIL) therapy for advanced melanoma, demonstrated durable efficacy in the 5‐year analysis of the C‐144‐01 trial, with an objective response rate (ORR) of 31.4% and prolonged responses in a heavily pretreated population. Real world data further supported its effectiveness, with higher ORR likely reflecting earlier lines of therapy and differences in patient selection. Preferentially expressed antigen in melanoma (PRAME)‐targeted T‐cell receptor (TCR) T‐cell therapy (anzu‐cel, IMA203) showed promising activity in a phase 1 study, with ORR of approximately 50% in checkpoint inhibitor refractory melanoma, durable responses, and manageable toxicity, validating PRAME as a high value target across multiple tumor types. Next‐generation engineered TIL approaches emerged to address limitations of high‐dose IL‐2. OBX‐115, an IL‐2 independent TIL platform expressing membrane‐bound IL‐15 regulated by acetazolamide, demonstrated early clinical activity with ORR of 67% in initial phase 1 data. Additional strategies, including CRISPR‐mediated gene editing and checkpoint disruption, highlight a shift toward programmable, self‐sustaining cellular therapies. Personalized neoantigen‐based therapies advanced with early clinical validation of adoptive T‐cell platforms and mRNA vaccines, demonstrating immune activation and improved recurrence‐free survival in melanoma. Finally, afamitresgene autoleucel (afami‐cel), a MAGE‐A4 directed TCR‐T therapy, showed durable efficacy in synovial sarcoma and expanding activity across solid tumors, establishing proof of concept for TCR‐T approaches. Collectively, these advances position autologous cellular therapy as an evolving standard of care in melanoma and a promising modality across solid tumors, with ongoing efforts focused on improving accessibility, overcoming resistance, and optimizing combinatorial strategies.

Short abstract

Autologous cellular therapy is rapidly evolving in solid tumors, with durable lifileucel outcomes, multiple emerging TCR‐T therapies, and engineered tumor‐infiltrating lymphocyte platforms, some already with preliminary data demonstrating improved efficacy and safety. These advances are expanding the clinical applicability of cell therapy and establishing it as an emerging standard across solid tumors.

INTRODUCTION

The year 2025 witnessed considerable progress in autologous cellular therapy for melanoma and solid tumors. Building on landmark regulatory approvals in 2024, the field rapidly advanced through engineering innovations and expanded clinical applications. In 2024, lifileucel was approved by the Food and Drug Administration (FDA) as the first tumor‐infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel for synovial sarcoma was the first T‐cell receptor (TCR) therapy approved. This review highlights five key advances in 2025: (1) long‐term efficacy and clinical integration of lifileucel TIL therapy, (2) preferentially expressed antigen in melanoma (PRAME)‐targeted TCR‐T therapy, (3) IL‐2–independent, programmable TIL therapies, (4) personalized neoantigen‐specific T‐cell therapies, and (5) expansion of afamitresgene autoleucel.

Advance 1: Long‐term efficacy data and clinical integration of lifileucel TIL therapy

The 5‐year analysis of the pivotal C‐144‐01 trial established lifileucel as a durable treatment option for appropriate patients with refractory metastatic melanoma. ¹ In heavily pretreated patients (median of three prior therapies), the objective response rate (ORR) was 31.4%, the complete response (CR) rate was 5.9%, and the partial response (PR) rate was 25.5%. Tumor burden was reduced in 79.3% of patients. At a median follow‐up of 60 months, the median duration of response (DOR) was 36.5 months, with 31.3% of responders maintaining ongoing responses at the 5‐year assessment time point. Sixteen patients experienced deepening responses over time (four patients with initial PR were determined to have CR more than 1 year after lifileucel infusion). Median overall survival (OS) was 13.9 months, with a 5‐year OS rate of 19.7%. The safety profile remained consistent with lymphodepletion and IL‐2 administration, with most grade 3/4 cytopenias resolving to grade ≤2 by day 30 and no new long‐term safety concerns.

Real‐world data demonstrated the effectiveness of lifileucel therapy in patients with advanced melanoma outside of clinical trials. Lifileucel demonstrated meaningful clinical activity and response rates: ORR was 44%, 39% patients had a confirmed partial response, and 5% with a confirmed complete response, with results likely reflecting differences in patient selection, including earlier lines of therapy and less heavily pretreated populations. These findings support the feasibility and effectiveness of lifileucel in real‐world practice. ² These data noted achievement in this treatment refractory advanced melanoma patient population. We eagerly await data from the ongoing phase 3 randomized TILAVANCE‐301 trial (NCT05727904), evaluating lifileucel plus pembrolizumab versus pembrolizumab alone in the first line for advanced melanoma. ³ Beyond melanoma, trials are investigating lifileucel in cervical, endometrial, head, and neck squamous cell (HNSCC), and non–small cell lung cancer (NSCLC), with early phase 2 data of IOV‐LUN‐202 trial (NCT04614103) in NSCLC showing feasibility and preliminary efficacy. ⁴ , ⁵

Advance 2: Anzu‐cel PRAME‐targeted TCR‐T therapy demonstrates breakthrough efficacy in melanoma

Anzu‐cel (IMA203), a PRAME (preferentially expressed antigen in melanoma) targeted TCR‐T therapy, emerged as another promising cellular therapy for solid tumors (Figure 1). ⁶ The phase 1 trial (NCT03686124) demonstrated efficacy in checkpoint inhibitor refractory melanoma, with a confirmed ORR of 50% in heavily pretreated patients (median, two prior therapies). ⁷

FIGURE 1.

Mechanism of action of anzu‐cel. Anzu‐cell is an autologous T‐cell receptor–engineered T‐cell therapy directed against preferentially expressed antigen in melanoma, an intracellular protein presented as peptide–human leukocyte antigen complexes on the surface of multiple solid tumors. ⁶⁰ Created in Biorender.

Tumor shrinkage occurred in 88% of patients, with seven of 14 confirmed responses ongoing beyond 2 years. ⁷ The median DOR was 12.1 months, and median OS was not reached at 8.6 months median follow‐up. ⁶ Anzu‐cel had a favorable safety profile; although cytokine release syndrome (CRS) was common (grade 1–2 in 83% patients), more severe toxicities were infrequent (grade 3 CRS in 11% patients, grade 1–3 immune effector cell‐associated neurotoxicity syndrome [ICANS] in 14%, and no grade 4–5 ICANS reported). No treatment‐related deaths occurred. ⁶ This catalyzed the SUPRAME trial (NCT06743126), a registration‐enabling randomized phase 3 trial comparing anzu‐cel to investigator’s choice in advanced checkpoint‐refractory melanoma. ⁸ A toxicity consideration unique to PRAME‐directed cellular therapy is testicular inflammation as a potential on‐target, off‐tumor adverse event, since PRAME expression among normal adult tissues is essentially restricted to testicular germ cells, where it is abundantly expressed. ⁹ , ¹⁰ Although orchitis was not reported in the phase 1 interim analysis, possibly reflecting testicular immune privilege and low germ cell human leukocyte antigen (HLA) class I expression, monitoring of gonadal function and fertility counseling in male patients remains prudent.

The success of anzu‐cel validates PRAME as a high value target, expressed in multiple other solid tumors, while having limited expression in normal tissues. ⁶ , ¹¹ In 15 evaluable patients with metastatic uveal melanoma, the phase 1b trial showed tentative clinical benefit with ORR 67%, median progression‐free survival (PFS) of 8.5 months at 14.3 months follow‐up, with a phase 2 expansion ongoing enabling larger cohorts and longer follow‐up. ¹² This represents a significant advance over prior melanoma TCR T‐cell therapies targeting cancer testis antigens. ¹³ , ¹⁴

Advance 3: IL‐2–independent, programmable TIL therapies

A major limitation of conventional TIL therapy is the required high dose IL‐2 administration after cell infusion, which causes significant toxicities of capillary leak syndrome, hypotension, and organ dysfunction and often restricts treatment to intensive care settings. ¹⁵ , ¹⁶ In 2025, genetically engineered TILs emerged as a transformative strategy to reduce or eliminate the dependence on IL‐2.

OBX‐115 represents the most clinically advanced IL‐2–free engineered TIL platform. OBX‐115 TILs are engineered to express membrane bound IL‐15 (mbIL15) fused to a drug responsive domain that is regulated by acetazolamide (ACZ), an FDA‐approved small molecule diuretic, enabling pharmacologic control of TIL activity without systematic IL‐2 (Figure 2). ¹⁷ , ¹⁸ The OBX‐115 cell product is manufactured with ACZ instead of IL‐2 in the presence of engineered feeder cells and exhibits ACZ dose‐dependent expansion and persistence both in vitro and in vivo. Another distinction from commercial lifileucel is the starting material requirement. Lifileucel manufacturing relies on surgical resection of a lesion at least 1.5 cm in diameter, whereas OBX‐115 can be generated from more limited tissue obtained by core needle biopsy, potentially broadening eligibility to patients without a resectable lesion of adequate size or for whom surgery may incur significant morbidity. ¹⁹

FIGURE 2.

Engineered T‐cell therapies enhance tumor infiltration, persistence, and antitumor activity. Overview of next‐generation engineered T‐cell strategies designed to overcome key limitations of conventional adoptive cell therapy. (Left) OBX‐115 TILs are engineered to express mbIL‐15 fused to a DRD, enabling pharmacologic control of cytokine signaling via ACZ. This approach promotes enhanced T‐cell survival, proliferation, and tumor infiltration without the need for systemic IL‐2. (Right) KSQ‐004EX CRISPR‐engineered T cells incorporate dual gene inactivation of SOCS1 and Regnase‐1, resulting in increased T‐cell expansion, improved persistence, and enhanced antitumor function. These distinct engineering strategies aim to increase tumor infiltration, sustain T‐cell persistence, and improve antitumor efficacy. Created in Biorender. ACZ indicates acetazolamide; DRD, drug‐responsive domain; mbIL‐15, membrane‐bound IL‐15; TIL, tumor‐infiltrating lymphocyte.

The Agni‐01 trial of OBX‐115 (NCT05470283) in patients with metastatic melanoma treated without any systemic IL‐2 demonstrated promising safety and early clinical activity. ¹⁸ In 2025, data were presented from the first 11 patients of this phase 1 multicenter dose‐escalation study (NCT06060613). In the six patients treated at the recommended phase 2 dose, ORR of 67% (four partial responses) and disease control rate (DCR) of 100% were achieved without IL‐2. At median follow‐up of 22.3 weeks, the median duration of response (DOR), PFS, and OS had not been reached. ²⁰ The trial is now in phase 2 in melanoma and phase 1 in NSCLC with reduced‐dose lymphodepletion followed by OBX‐115 infusion and ACZ dosing on days 0–6 and 14–20 followed by longitudinal ACZ redosing at periodic intervals until week 24 and optional redosing on progression. ²¹

Beyond OBX‐115, CRISPR‐engineered TIL platforms are emerging as potential IL‐2 independent strategies. KSQ‐004EX uses CRISPR/Cas9 to dually inactivate SOCS1 and Regnase‐1, to enhance T‐cell tumor infiltration, persistence, and efficacy (Figure 2). ²² , ²³ A phase 1/2 trial (NCT06598371) is enrolling patients with melanoma, NSCLC, head and neck squamous cell carcinoma, pancreatic, colorectal, and cervical cancer, with initial dose escalation cohorts including some patients not receiving IL‐2. ²⁴

Other gene editing approaches include the TALEN‐mediated programmed cell death protein 1 (PD‐1) knockout TIL (IOV‐GM1‐201) trial, ongoing in melanoma and NSCLC (NCT05361174), which has shown favorable safety profiles with no evidence of compensatory exudation pathway activation (Figure 3). ²⁵ The phase 1/II trial of IOV‐3001 in combination with lifileucel in (NCT06940739) is ongoing. IOV‐3001 is an engineered IL‐2 fusion protein with a prolonged half‐life (∼5–8 hours), in vitro activity comparable to IL‐2, and a favorable preclinical safety profile (Figure 3). ²⁶ The convergence of synthetic biology and TIL therapy represents a paradigm shift toward programmable, self‐sustaining cellular products with the potential for improved safety and efficacy profiles.

FIGURE 3.

Engineering strategies enhance TIL function through checkpoint disruption and cytokine support. Two distinct approaches to improve TIL efficacy. (Left) TALEN‐mediated PD‐1 knockout TILs (IOV‐GM1‐201) are generated via targeted disruption of PD‐1, resulting in loss of PD‐1 receptor expression and reduced PD‐1/PD‐L1–mediated inhibitory signaling within the tumor microenvironment. This enhances T‐cell activation and cytotoxicity by preventing checkpoint‐dependent TIL inactivation. (Right) IOV‐300 is an engineered dimeric IL‐2 protein fused to palivizumab designed to selectively deliver cytokine signaling to the tumor microenvironment, promoting TIL proliferation and functional activity. Created in Biorender. PD‐1 indicates programmed cell death protein 1; PD‐L1, programmed death‐ligand 1; TIL, tumor‐infiltrating lymphocyte.

Advance 4: Personalized neoantigen‐specific T‐cell therapies advance toward clinical reality

Neoantigen‐based cellular therapies targeting patient‐specific tumor mutations are a highly promising precision immunotherapy approach, with multiple platforms demonstrating proof of concept. ²⁷ , ²⁸ , ²⁹ The BNT221 trial reported results from personalized, autologous neoantigen‐specific T cells derived from peripheral blood in nine patients with metastatic melanoma who progressed after checkpoint inhibitors. ³⁰ No dose limiting toxicities, CRS, or neurotoxicity reported. Six of nine patients achieved stable disease with tumor reductions up to 20%.

The NEO‐STIM platform systematically generated T‐cell responses against personalized neoantigens from autologous peripheral blood. ³¹ The ex vivo induction primes and expands preexisting memory and de novo CD4⁺ and CD8⁺ T cells recognizing autologous tumor material. A phase 1 trial (NCT04625205) validated proof of concept, with T‐cell responses detected in tumor and blood post‐infusion displaying activated/exhausted and cytotoxic phenotypes. ³⁰

mRNA‐4157, a personalized mRNA vaccine encoding up to 34 patient‐specific neoantigens demonstrated clinical benefit when combined with pembrolizumab in the randomized phase 2b KEYNOTE‐942 trial. ³² In 157 patients with high‐risk resected melanoma, the combination showed clinically meaningful improvement in recurrence‐free survival compared to pembrolizumab monotherapy, with a favorable safety profile, leading to the phase 3 registrational study (V940‐001, NCT05933577). ³³

Challenges remain in neoantigen prediction accuracy, manufacturing timelines (typically 8–12 weeks), and optimal delivery platforms. ²⁷ , ²⁸ , ³⁴ However, advances in high throughput sequencing and multi‐omics integration are accelerating progress. The convergence of neoantigen vaccines creating neoantigen rich TILs or TCR T cells represents a promising future direction. ³⁵

Advance 5: Afamitresgene autoleucel expands TCR‐T therapy beyond synovial sarcoma

Following the 2024 FDA approval for synovial sarcoma, afamitresgene autoleucel (afami‐cel), a MAGE‐A4–directed TCR T‐cell therapy, continued to demonstrate durable efficacy and is expanding to additional indications. ³⁶ , ³⁷ In the pivotal SPEARHEAD‐1 trial (NCT04044768), afami‐cel achieved an ORR of 39% in synovial sarcoma patients (median three prior lines of therapy), and median DOR of 11.6 months. ³⁷ At 32.6 months median follow‐up, median OS was 15.4 months, with 12‐month and 24‐month OS probabilities 60% and 40%, respectively. Among responders, median OS was not reached, with 12‐ and 24‐month OS rates of 90% and 60%, respectively. The safety profile was manageable, with grade 1–2 CRS in 71% patients and only one grade 3 CRS event. ³⁷ Cytopenias were the most common grade 3+ adverse events; no treatment‐related deaths occurred. ³⁸

The approval of afami‐cel established proof of concept for TCR T‐cell therapy in solid tumors and validated cancer testis antigen as viable targets. ¹⁴ MAGE‐A4 is expressed (50%–90%) on multiple solid tumor types including melanoma, ovarian, and head and neck cancers. ³⁹ , ⁴⁰ , ⁴¹ The phase 1 trial of afami‐cel included these tumor types, with encouraging preliminary activity. ⁴² The therapy requires HLA‐A*02:01, HLA‐A*02:02, HLA‐A*02:03, or HLA‐A*02:06 positivity and MAGE‐A4 expression confirmed by companion diagnostic. ³⁶ Afami‐cel also showed modest activity in myxoid round cell liposarcoma (MRCL) with an ORR of 25%. ³⁷ Success with afami‐cel springboarded the development of TCR‐T therapies targeting cancer testis antigens, including NY‐ESO‐1–directed products showing response rates of 39%–61% in synovial sarcoma and MRCL. ⁴³ The field is also exploring strategies to overcome HLA restriction through multi‐HLA targeting, improving tumor microenvironment penetration through chemokine receptor engineering, and enhancing persistence through checkpoint disruption. ⁴⁴ , ⁴⁵

FUTURE DIRECTIONS AND CHALLENGES

The recent advances in autologous cellular therapy have positioned it as an established treatment modality for melanoma and synovial sarcoma, and as an emerging and viable option across diverse solid tumors. However, significant challenges remain. Manufacturing complexity and cost limit accessibility, with TIL and TCR‐T production requiring 3–6 weeks and specialized facilities. ⁴⁶ , ⁴⁷ Antigen heterogeneity and escape remain major resistance mechanisms, driving interest in dual antigen targeting and combination approaches. ⁴⁸ , ⁴⁹ , ⁵⁰ A key limitation of existing solid tumor cell therapies is treatment intensity, particularly requirements for nonmyeloablative lymphodepletion and high‐dose IL‐2 for lifileucel, which drives the majority of severe toxicities. Lifileucel is restricted to patients with adequate cardiac, pulmonary, and renal function, absence of active central nervous system metastasis, and good performance status, which represents only a fraction of patients with checkpoint‐refractory melanoma. Based on promising preliminary data, OBX‐115 may represent a meaningful advance in by using reduced‐intensity lymphodepletion and less‐invasive tumor procurement techniques and obviating the need for high‐dose IL‐2, innovations with the potential to extend cell therapy to a substantially larger proportion of patients with solid tumors.

The immunosuppressive tumor microenvironment continues to impede cellular therapy efficacy in many solid tumors. Strategies under investigation include checkpoint gene disruption (PD‐1, TIM‐3, and LAG‐3 knockout), metabolic reprogramming to enhance T‐cell fitness, chemokine receptor engineering to improve trafficking, and combination with oncolytic viruses or radiation to remodel the microenvironment. ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ CRISPR‐based gene editing is enabling multiplex modifications to created armored T cells with enhanced functionality, reduced exhaustion, and improved safety profiles. ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹

Looking forward, rational combinations and sequencing with checkpoint inhibitors, targeted therapies, and other immunomodulatory agents will be critical to maximizing treatment efficacy. The recent advances have catapulted autologous cellular therapy from an experimental approach to an evolving standard of care in melanoma and potentially transformative option for select solid tumors. With continued innovation in engineering, manufacturing, and clinical application, these therapies are poised to reshape the treatment landscape with the potential for durable responses to one‐time therapy.

AUTHOR CONTRIBUTIONS

Kimberly Loo: Data curation, investigation, methodology, validation, writing–original draft, and writing–review and editing. Allison S. Betof: Conceptualization, data curation, formal analysis, investigation, methodology, resources, supervision, validation, visualization, writing–original draft, and writing–review and editing.

CONFLICT OF INTEREST STATEMENT

Allison S. Betof reports consulting fees from Adaptimmune, BluePath Solutions, Bristol‐Myers Squibb/Medarex, cTRL Therapeutics, Genmab, Immatics, IO Biotech, Iovance Biotherapeutics, Merck, Novartis, Obsidian Therapeutics, Pfizer, and Replimune; and grant and/or contract funding from Bristol‐Myers Squibb/Medarex, Immatics, Immunocore, Iovance Biotherapeutics, Lyell Immunopharma, Obsidian Therapeutics, and Replimune. The other author declares no conflicts of interest.