Women occupy a minority of academic leadership positions despite increasing representation in the physician workforce. Similarly, women remain underrepresented as academic conference presenters, an important factor for career advancement. We examined whether there were gender disparities in opportunities to present original research at the ASCO Annual Meeting. We retrospectively reviewed oral original research, educational, and discussant presentations at the ASCO Annual Meetings from 2018 to 2021. Presenters were identified as first author, senior author, or ASCO-appointed (chair, discussant, or speaker). Presenter-identified gender was unavailable; binary gender was determined by presenter name, pronouns, video files, and institutional websites. Presenter gender distributions were summarized descriptively by nominal levels for each third variable with corresponding odds ratios (ORs) for each nominal level. Common ORs were estimated for each third variable if the Breslow-Day test was not significant, with no adjustments for P values. We reviewed 4,267 video presentations, divided into original research (n = 2,079) and ASCO-appointed (n = 2,188). Women represented 37% of first authors (OR, 0.68 [95% CI, 0.60 to 0.76]) and 28% of senior authors (OR, 0.44 [95% CI, 0.39 to 0.50]), compared with 47% of ASCO-appointed presenters. Women were significantly more likely to have an ASCO-appointed role than a first or senior author role, even after adjusting for conference year, session type, session area, academic rank, and geographic region. Gender disparities persist in opportunities to present original research at the ASCO Annual Meeting. Women were less likely to present research as first or senior author and were more likely to have an educational or discussant role. As high-profile original research can elevate careers, examining factors contributing to this disparity may suggest approaches to address gender leadership gaps in oncology.

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro1,2. In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-Gα13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, Gαs, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.

Exercise is recommended as a part of standard cancer care, based upon its favorable impact on treatment-related side effects and its association with better cancer outcomes. Fully incorporating exercise into oncology practice will require multidisciplinary efforts across oncology and exercise professionals. This article examines current patterns of exercise advice and prescription in oncology settings and highlights the roles of oncology clinicians, physiatrists, physical and occupational therapists, exercise physiologists and fitness trainers, and patient advocates in expanding exercise oncology across the cancer continuum. Future efforts to enhance provider education, expand community-based programs, establish referral pathways, and address policy challenges related to reimbursement will be needed to establish exercise as a universally accessible and effective component of oncology care.

Non-engineered TIL cell therapy was recently approved for patients with immune checkpoint inhibitor (ICI)-resistant melanoma (Chesney JITC 2022) and shows promising efficacy in non-small cell lung cancer ([NSCLC]; Creelan Nat Med 2021, Schoenfeld Cancer Discov 2024), but has a treatment-related mortality rate of 7.5% in melanoma and requires co-administration of systemic high-dose IL2, with well-described high-grade toxicity. OBX-115 TIL are expanded from patient tumor tissue and engineered with a transgene to express membrane-bound human IL15 (mbIL15), regulated by acetazolamide (ACZ), eliminating the need for IL2. A first-in-human single-institution study evaluating the safety of OBX-115 in metastatic melanoma has completed enrollment (NCT05470283; Amaria ASCO 2024). The current study (NCT06060613) is enrolling patients with melanoma and NSCLC at multiple US sites using centralized manufacturing. This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in patients with unresectable Stage IIIC-IV metastatic melanoma (excluding uveal) with radiographic progression after systemic therapy containing PD-1-targeted ICI (≤2 prior lines; neoadjuvant/adjuvant considered prior line if progressed during treatment or within ≤12 weeks of last dose) OR metastatic NSCLC previously treated with an approved systemic therapy for metastatic disease (including an ICI-based regimen and/or targeted therapy where applicable) and progressed, no longer deriving benefit, or unable to continue due to treatment intolerance. Patients may have treated and asymptomatic brain metastases and must have ECOG PS of 0 or 1, life expectancy >∼6 months, ≥1 lesion suitable for OBX-115 manufacturing, and ≥1 RECIST v1.1-measurable lesion remaining after tumor tissue procurement. Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of OBX-115 + ACZ; Phase 2 will evaluate efficacy of the regimen (ORR using RECIST v1.1 per investigator). Melanoma RP2D has been determined and is in Phase 2; NSCLC is in Phase 1. Cryopreserved OBX-115 is generated from the patient’s own tumor tissue procured by surgical excision or core needle biopsy and is infused after standard- or low-dose lymphodepletion (cyclophosphamide and fludarabine) based on clinical status and prior treatments. No IL2 is administered. ACZ is administered at cohort-defined doses once daily starting day of OBX-115 infusion for ≤14 days (split into two ≤7-day periods within 28 days), with additional ACZ dosing for ≤7 days at weeks 5, 11, 17, and 23, or upon progression when new anticancer therapy is not immediately warranted. Eight sites are open and recruiting, with additional sites being activated. Alexander N. Shoushtari, Adam J. Schoenfeld, Kai He, Jason A. Chesney, Juan Carlos Varela, Justin T. Moyers, Gino K. In, Yazan Samhouri, Rodabe N. Amaria, Parameswaran Hari, Giridharan Ramsingh, Camille Renard, Prakash Prabhakar, Lauren Mclaughlin, Mercay Reuter, Allison Betof Warner. Trial in progress: Phase 1/2 study of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT244.

BACKGROUND/OBJECTIVES:Uveal melanoma is a rare but aggressive intraocular malignancy that metastasizes in up to half of patients, most commonly to the liver, despite effective local treatment. In the absence of robust evidence, there are no standardized guidelines for post-treatment surveillance, resulting in wide variation in imaging modalities, frequency, and duration across physicians and institutions. This study aimed to develop expert consensus recommendations for surveillance strategies in patients with uveal melanoma. METHODS:A modified Delphi method was conducted across three iterative survey rounds between September 2024 and February 2025 using an online platform. Panelists included medical oncologists, ocular oncologists, radiologists, and surgical oncologists from North America. A multidisciplinary steering committee developed statements addressing risk-based surveillance using both molecular and clinical prognostic factors, including gene expression profiling (GEP) and PRAME status. Consensus was defined a priori as ≥70% of panelists rating a statement 7-9 on a 9-point Likert scale. RESULTS:Forty-nine experts were invited, and 41 completed at least one survey round. The panel represented 17 U.S. states, Washington, D.C., and two Canadian provinces. Twelve statements reached stable consensus, including recommendations for imaging modality, frequency, and duration in intermediate- and high-risk patients. Although there was agreement that low-risk patients warrant surveillance, no consensus was reached on the optimal approach for this group. CONCLUSIONS:This is the first study to provide consensus-based guidance incorporating GEP and PRAME status into surveillance recommendations for uveal melanoma, offering a standardized framework to guide clinical practice and future research.

Importance:Leptomeningeal metastasis (LM) is associated with limited survival and few treatment options. Photon involved-field radiotherapy (IFRT) is the most common radiotherapy treatment for patients with LM from solid tumors. Objective:To assess whether proton craniospinal irradiation (pCSI) would result in superior central nervous system progression-free survival (CNS-PFS) compared with IFRT. Design, Setting, and Participants:A randomized, phase 2 trial of pCSI vs IFRT was conducted between April 16, 2020, and October 11, 2021, and included patients with non-small cell lung cancer and breast cancer with LM. Patients with other solid tumors were also enrolled in an exploratory pCSI cohort. Intervention:For the randomized groups, after stratifying by histology and systemic disease status, patients were assigned (2:1) to pCSI or IFRT. Main Outcomes and Measures:The primary end point was CNS-PFS. Secondary end points included overall survival (OS). Results:Of 98 total patients, 72 individuals (73.5%) were female, and the median (IQR) age was 59 (50-65) years. A total of 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In this final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median, 8.2 months; 95% CI, 6.6-15.3) vs IFRT (median, 2.3 months; 95% CI, 1.2-4.0; P < .001). A statistically significant and clinically meaningful OS benefit with pCSI (median, 11.3 months; 95% CI, 7.5-18.3) vs IFRT (median, 4.9 months; 95% CI, 3.9-15.0; P = .04) was also observed. For the exploratory pCSI cohort (n = 35), the median CNS-PFS was 5.8 months (95% CI, 4.4-9.1) and OS was 7.0 months (95% CI, 5.4-10.6). Conclusions and Relevance:This randomized clinical trial that assessed the optimal radiotherapy treatment for LM found improved CNS-PFS and OS with pCSI compared with IFRT. The results suggest that pCSI should be considered when available. Trial Registration:ClinicalTrials.gov Identifier: NCT04343573.

Abstract Background:Immunotherapy continues to revolutionize melanoma treatment. The major side effects of ICIs are irAEs, where off-target immune activation damages healthy tissues. Management of irAEs is immunosuppression. The first TIL therapy, lifileucel, recently gained FDA approval for patients with melanoma refractory to ICI. Adverse events from lifileucel are largely driven by lymphodepletion and IL-2. However, patients may have pre-existing irAEs that could flare in the TIL-induced hyperinflammatory state. Steroids are avoided in the peri-TIL setting given their suppressive impact on effector T-cells and concern for impaired anti-tumor efficacy. Case:We present a 78-year-old female with metastatic acral lentiginous melanoma. She was initially diagnosed with stage IIIC BRAF wild type melanoma and underwent resection and 3 cycles of adjuvant pembrolizumab until disease progression. She then received 2 cycles of ipilimumab/nivolumab then 4 cycles on a clinical trial of GIM-122, a dual functioning monoclonal antibody acting on the PD-1 pathway. She tolerated treatment with mild side effects but had refractory disease. Within a month post treatment discontinuation, she developed nausea and weight loss refractory to antiemetics. CT abdomen and MRI brain were nonrevealing. EGD showed erythema in the gastric antrum and pyloric ulcer; pathology showed increased crypt apoptosis, increased intraepithelial lymphocytes, and villous blunting consistent with ICI gastritis and duodenitis. She received 1 dose of infliximab with symptom resolution then proceeded with lifileucel. She received 3/6 doses of IL-2 until discontinuation for tachyarrhythmia and hallucinations, which resolved with discontinuation. Her GI symptoms flared post-lifileucel, so she started oral budesonide and vedolizumab for GI-targeted immunosuppression to minimize effects on systemic immunity. Repeat biopsies showed minimal crypt apoptosis in the duodenum and chronic active gastritis. Her 6-week post TIL scans showed mixed response. At 8 weeks post-TIL she received a dose of systemic steroids for refractory symptoms. Scans 10 weeks post-TIL showed progressive disease, and her GI symptoms were palliated with systemic steroids. Discussion:This case describes a patient with history of ICI exposure and irAE who proceeded with TIL therapy after which her irAE symptoms flared. Given desire to preserve the TILs’ anti-tumor efficacy, non-steroid agents were initially pursued. Steroids suppress the innate and adaptive immune system by decreasing leukocyte adhesion, promoting an immunosuppressive cytokine milieu, and downregulating effector T-cells with upregulation of regulatory T-cells. Preclinical evidence suggests steroids impair anti-tumor efficacy of TILs whereas anti-TNF agents have less impact. Patients may enter TIL therapy with an irAE history or develop them during treatment, particularly given ongoing studies combining ICI and TILs. It is not clear how to best manage irAEs peri-TIL therapy. More research is needed to understand how immunosuppressants impact the efficacy of TILs. Citation Format: Alicia H Darwin, Karen C Kim, Amanda R Kirane, Pauline Funchain, Allison Betof Warner. Managing Immune-Related Adverse Events (irAEs) During Tumor Infiltrating Lymphocyte (TIL) Therapy: Insights from a Case of Refractory Immune Checkpoint Inhibitor (ICI)-Induced Gastritis [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A125.

TPS2673 Background: Frequent recurrence and limited long-term survival in unresected or metastatic melanoma after relapse from 1L treatment with a checkpoint inhibitor (CPI) highlight the critical need for new therapies that deliver deeper, more durable responses (Knight Cancers 2023; Switzer JCO Oncol Pract 2022). ACTengine IMA203 is an autologous T cell receptor (TCR)-engineered T cell therapy (TCR-T) targeting PRAME, an intracellular protein displayed as peptide antigen at high density on the surface of multiple solid tumors, including melanoma. IMA203 TCR-T demonstrated a favorable tolerability profile and durable objective responses in heavily-pretreated patients with different tumor types. In melanoma, IMA203 showed 54% confirmed ORR (14/26), 12.1 months mDOR and 6 months mPFS. mOS was not reached at a mFU of 8.6 months (Wermke et al., SMR, Oct 10, 2024). Based on these observations, a registration-enabling randomized phase 3 trial, SUPRAME, was initiated to evaluate IMA203 in 2L patients with advanced cutaneous melanoma after treatment with a CPI. Methods: SUPRAME (NCT06743126) is a phase 3, multicenter, open-label, randomized, actively controlled, parallel-group trial that will evaluate the efficacy, safety and tolerability of IMA203 compared to investigator's choice of treatment in patients with previously treated, unresectable or metastatic cutaneous melanoma (incl. acral melanoma). Eligible patients are ≥18yo, HLA-A*02:01-positive, with measurable disease (RECIST v1.1), ECOG PS of 0-1 and disease progression on or after at least one PD-1 inhibitor. Patients with BRAF mutation should have been treated with one prior line of BRAF-directed therapy (± MEK inhibitor) prior to initial eligibility assessment. Patients with asymptomatic stable brain or leptomeningeal metastases will be assessed for eligibility. Patients with active brain metastases or with primary mucosal, uveal melanoma and melanoma of unknown primary are excluded. The study will randomize ~360 patients 1:1. Patients in the experimental arm will undergo leukapheresis to generate the PRAME-specific TCR-T product, IMA203. Following lymphodepletion with cyclophosphamide (500 mg/m 2 x 4 days) and fludarabine (30 mg/m 2 x 4 days), 1-10x10 9 IMA203 TCR-T cells will be administered, followed by low-dose IL-2 (1mio IU daily x5 days, twice daily x5 days). Patients in the control arm will receive approved investigator’s choice of standard treatment (nivolumab/relatlimab, nivolumab, ipilimumab, pembrolizumab, lifileucel (US), chemotherapy). The primary efficacy endpoint is BICR-assessed (RECIST v1.1) PFS. Secondary endpoints include OS, ORR, safety and patient-reported outcomes (EORTC QLQ-C30, EQ-5D-5L). The trial will enroll patients in the US and Europe. Clinical trial information: NCT06743126 .

Immune checkpoint blockade (ICB) has revolutionized outcomes for patients with melanoma across multiple disease settings. In patients with advanced, unresectable disease, the ICB combination of nivolumab (anti-PD1) and relatlimab (anti-LAG-3) has demonstrated improved clinical outcomes compared with nivolumab monotherapy. There exists an unmet need to identify biomarkers that predict response to this combination regimen and rational therapeutic strategies to overcome resistance. We previously reported the initial results of a phase II clinical trial (ClinicalTrials.gov identifier: NCT02519322) of neoadjuvant systemic treatment (NST) followed by adjuvant treatment with nivolumab and relatlimab, which achieved a major pathologic response (MPR; ≤10% viable tumor) rate of 63% in patients with stage III/IV, surgically resectable melanoma. Our updated clinical follow-up (median 47 months) for these patients demonstrates that at 4 years from the start of NST, 80% of patients remain event-free, including 95% of patients who achieved a MPR. Gene expression analysis of longitudinally collected biospecimens from the trial identifies baseline upregulation of several immune modulatory pathways associated with MPR; by contrast, increased B7-H3 expression was associated with resistance. This work demonstrates the long-term benefit of neoadjuvant nivolumab and relatlimab and identifies a potentially targetable predictor of resistance to this combination therapy.

Programmed death ligand-1 (PD-L1) is an inducible protein heterogeneously expressed in melanoma. Assessment of PD-L1 expression is challenging and standard immunohistochemistry (IHC) requires biopsies and cannot capture heterogeneity of expression. Noninvasive imaging methods provide evaluation of expression across lesions in the body. We conducted a prospective pilot trial with PD-L1 PET imaging with [ 18 F]-BMS-986229 as a noninvasive approach to assess PD-L1 expression across lesions, in 10 patients with advanced melanoma, longitudinally during treatment with nivolumab and ipilimumab. PET imaging was performed at baseline and at 6 weeks after-initiation of treatment. We examined the relationship of PD-L1 PET uptake to radiographic clinical response. [ 18 F]-BMS-986229 uptake was variably seen across lesions in patients at baseline. All patients showed positive uptake in lesions at baseline PET with a median SUV max of 3.6 (range: 1.7–8.6). PD-L1 PET SUV max decreased in all but two lesions 6 weeks after treatment initiation. Four of five patients had a mean (SUV max ) greater than or equal to 3.00 in Response Evaluation Criteria in Solid Tumors (RECIST) evaluable lesions at baseline, and all had a RECIST response while all progressors ( n = 3) had baseline PD-L1 mean SUV max less than or equal to 2.60. A higher lesional baseline SUV max was associated with greater individual lesion reduction during treatment. The PD-L1 uptake in lesions showed a low correlation with baseline PD-L1 by IHC. In this small pilot study, PD-L1 PET imaging using [ 18 F]-BMS-986229 showed feasibility in noninvasively assessing lesion uptake and PD-L1 heterogeneity in patients receiving combination immunotherapy. Future exploration of this tracer in larger patient cohorts is necessary to delineate its use in managing immunotherapy treatments.

The recent approval of lifileucel by the US Food and Drug Administration in February 2024 was the culmination of over 3 decades of research in adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) for unresectable melanoma. In this review, we highlight key historical data for TIL therapy in melanoma as well as ongoing efforts to improve its efficacy and applicability.

Adoptive cellular therapy (ACT) is an increasingly widely used treatment approach for malignancy. While infectious complications of ACT have been well described in patients with hematologic malignancies, limited data are available on the epidemiology of infections in patients with solid tumors. The purpose of this study was to describe the epidemiology of infections occurring within the first 180 days in adult patients with solid tumors treated with ACT and to identify risk factors predisposing these patients to infection. Data on 132 adult patients with solid tumors undergoing ACT between August 2014 and November 2021 at Memorial Sloan Kettering Cancer Center were collected. Infections were documented from the day of ACT infusion through day 180 postinfusion. Overall, 28 of 132 patients (21.2%) experienced 33 infections within the first 30 days of ACT, and 17 of 131 surviving patients (13%) were diagnosed with 24 infections between day 31 and day 180. Infection-related mortality was low. The majority of infections were bacterial. While male gender, older age, Eastern Cooperative Oncology Group (ECOG) performance status (PS) at time of ACT infusion, tocilizumab receipt, and cytokine release syndrome treated with tocilizumab were associated with shorter time to first infection on univariable analysis, only ECOG PS and tocilizumab receipt remained independent risk factors in the multivariable analysis. The proportion of patients with solid tumors experiencing early or late infections after ACT was lower compared to that reported among patients with B cell malignancies after chimeric antigen receptor T cell therapy. Most observed infections were primarily bacterial with low infection-related mortality; the incidence of viral and fungal infections was low. Based on the low frequency and timing of infections relative to neutropenia, antibacterial and antifungal prophylaxis are not likely to be beneficial. ECOG PS ≥2 and tocilizumab receipt were identified as significant predictors for infection after ACT, likely signaling an individual's debilitated state that predisposes to infection. Additional work to parse out confounders is needed to better identify risk factors for infection.

TPS9597 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy, accounting for nearly 90% of ocular melanomas and up to 5% of melanomas overall. Approximately 50% of patients (pts) with UM will develop metastatic disease, with the liver being the most common site of metastases (~90%). The prognosis for pts with metastatic UM (mUM) is poor, with a median overall survival (OS) of approximately 1 year. Effective treatment options for mUM are limited as it responds poorly to single-agent immune checkpoint inhibitors (ICIs; <10% response rate). Response rates are slightly higher with combination therapies (12%–18%), but often at the expense of increased toxicity. Tebentafusp is FDA approved for mUM based on survival benefit; however, its use is restricted to pts who are HLA-A*02:01 positive, and only ~10% of pts achieve an objective response. RP2 is a selectively replication-competent herpes simplex virus type 1–based oncolytic immunotherapy expressing GM-CSF, a fusogenic glycoprotein (GALV-GP-R–), and an anti–CTLA-4 antibody-like molecule. Prior phase 1 preliminary clinical data of RP2 as monotherapy or in combination with nivolumab (nivo) demonstrated a promising safety profile and anti-tumor activity with an ORR of 29.4% in 17 patients with mUM, most of whom had received prior ICIs. This study will assess the efficacy and safety of RP2 + nivo vs ipilimumab (ipi) + nivo in pts with ICI-naïve mUM (NCT06581406; RP2-202). Methods: This is a randomized, controlled, phase 2/3 study. Key eligibility criteria include age ≥18 years and confirmed unresectable mUM with lesions amenable to injection. Pts with metastatic disease who have had prior exposure to ICIs since the time of UM diagnosis, involvement of >33.3% of the liver, or a history of prior liver- or lesion-directed therapy are not eligible for enrollment. Enrolled pts (N = ~280) will be randomized 1:1 to receive either RP2 + nivo or ipi + nivo. In the RP2 + nivo arm, RP2 will be given intratumorally initially at 1 x 10 6 PFU/mL, then every 2 weeks (Q2W) at 1 x 10 7 PFU/mL for 7 doses in combination with intravenous (IV) nivo (240 mg). In the ipi + nivo arm, pts will receive IV ipi (3 mg/kg) and IV nivo (1 mg/kg) Q3W for 4 doses. Pts in both arms may then receive IV nivo at 240 mg Q2W or 480 mg Q4W for up to 2 years from the first dose. The co-primary endpoints are OS and progression-free survival by independent central review using RECIST 1.1. Secondary endpoints are overall response rate, duration of response, disease control rate, clinical benefit rate, duration of clinical benefit, and safety, including incidence of treatment-emergent adverse events (AEs), serious AEs, and immune-mediated AEs. Clinical trial information: NCT06581406 .

9517 Background: OBX-115 TIL are engineered to express mbIL15 regulated by the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for toxic high-dose IL2 after TIL infusion. Single-center phase 1 data (NCT05470283) demonstrated differentiated early safety (Amaria ASCO 2024). We report the first data evaluating OBX-115 in pts with advanced melanoma in the multicenter phase 1/2 Agni-01 study (NCT06060613). Methods: This single-arm, open-label study assesses safety, tolerability, and efficacy of the OBX-115 TIL cell therapy regimen in pts with advanced melanoma and NSCLC (Shoushtari AACR 2025). Phase 1 characterizes safety (treatment-emergent adverse events [TEAEs]: AEs ≤30 d after OBX-115 infusion) and tolerability in escalating dose levels of OBX-115 and ACZ to establish a recommended phase 2 dose (RP2D). Phase 2 evaluates efficacy of the regimen at RP2D (RECIST v1.1 per investigator). OBX-115 is manufactured from pt tumor tissue (core needle biopsy or surgical excision) and infused after standard- or low-dose (Cy 750 mg/m 2 /d × 3; Flu 30 mg/m 2 /d × 4) lymphodepletion (LD). No IL2 is administered. Oral ACZ starts day of OBX-115 infusion (QD up to 14 d), and is redosed (QD up to 7 d) every 6 wks after recovery from LD. Results: In phase 1,as of 01 Jan 2025, OBX-115 was successfully manufactured and infused for 11 pts with ICI-resistant advanced melanoma (median study follow-up, 22.3 wks [range, 13.3–52.1]) including 6 treated at RP2D (OBX-115 1–100×10 9 cells, ACZ 500 mg/d). Majority (n = 10) received low-dose LD, including 1 in the outpatient setting. There was no dose-limiting toxicity (DLT), treatment-emergent ICU transfer, or treatment-related mortality (TRM). Eight pts had G≥3 nonhematologic TEAEs (events in > 1 pt: hyponatremia, hypokalemia [n = 2 each]). One pt reported 2 OBX-115–related serious AEs, including 1 CRS event (G2) without IL6 elevation (IL6 < 100 pg/mL). Across dose levels (n = 11), confirmed ORR was 36% (4 PR, 5 SD; DCR 82%). For 6 pts receiving RP2D, ORR was 67% (4 PR, 2 SD; DCR 100%). Conclusions: Early data support clinical benefit (RP2D ORR 67%, DCR 100%) of OBX-115regulatableengineeredTIL cell therapy in the absence of IL2, including with outpatient low-dose LD. The safety profile is highly differentiated, without TRM, ICU transfer, or high-grade CRS. ACZ redosing is well-tolerated and offers an opportunity to deepen responses by inducing re-expression of mbIL15 on engrafted OBX-115 TIL, a unique capability among adoptive cell therapies. These attributes may comprehensively address the unmet need in post-ICI advanced melanoma and other cancers, and data support continued investigation of OBX-115 in the ongoing phase 2 portion of the Agni-01 study. Clinical trial information: NCT06060613 .

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs.A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements.Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Interleukin-2 (IL-2) was one of the first immunotherapies in the treatment of patients with cancer. High-dose bolus IL-2 (HD IL-2) can induce durable complete or partial tumor regression in a small proportion of advanced melanoma and renal cell carcinoma patients. However, its potential for life-threatening side effects and requirement for inpatient administration limits its use to patients with excellent organ function treated at experienced centers. In 2024, following decades of foundational work at the National Cancer Institute, lifileucel became the first FDA-approved tumor-infiltrating lymphocyte (TIL) therapy for cancer. HD IL-2 is routinely given after TIL infusion to promote the survival and proliferation of the T cell product. In this context, fewer doses are given, and the parameters for holding an IL-2 dose are more conservative, as compared with HD IL-2 monotherapy, which has now fallen out of routine use. The lower number of doses, and possibly the effects of the preparative lymphodepletion, result in much less cytokine-related toxicity. Nevertheless, concerns related to HD IL-2 toxicity persist and possibly impact decisions to offer TIL when indicated. Here, we discuss the differences in the administration of HD IL-2 as a monotherapy vs an adjunctive therapy following TIL infusion, in an effort to demystify the toxicity of HD IL-2 in the era of cellular therapy.