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Abstract Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint–related endocrinopathies.

BackgroundThe combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur.Case presentationWe describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy.ConclusionsThis case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.

Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced stage non-small cell lung cancer (NSCLC). However, little is known about the safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and stereotactic radiation for the treatment of brain metastases. Data were analyzed retrospectively from NSCLC patients treated with stereotactic radiation either before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49 brain metastases over 21 sessions were identified. Radiation was administered prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13 lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan–Meier (KM) distant brain control rate was 48% following stereotactic radiation. Six and 12 month KM rates of OS from the date of stereotactic radiation and the date of cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month rate of distant brain control following stereotactic radiation for patients treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90 was found to be predictive of worse OS following radiation treatment on both univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two modalities can be used synergistically to improve distant brain control and OS is warranted.

Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3–48.6) and 43.3% of arm C (95% CI 23.9–65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7–46.3), 16.7% (95% CI 2.9–49.1), and 23.8% (95% CI 9.1–47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.

Background Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer. Methods An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI. Results Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA ( p  < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3–5.0) and overall survival was 14.7 months (95% CI, 8.5–20.9). Conclusions The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70–2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.

Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS -mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS -mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations ( KRAS and EGFR) and tumor suppressor mutations ( STK11 and TP53 ), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11 , but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS -mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

BackgroundMesothelin (MSLN) is overexpressed in many cancer types. Loss of heterozygosity (LOH) may provide a means to target tumor versus normal cells1 and to augment the efficacy and safety of MSLN-targeted programs2–4. A2B694 is an autologous, logic-gated, Tmod CAR T therapy to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR T activator with a human leukocyte antigen (HLA)-A*02 blocker (figure 1)5 6.MethodsThe first-in-human, open-label, phase 1/2 EVEREST-2 study is evaluating safety and efficacy of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose (RP2D). Phase 2 primary objective: assess overall response rate.ResultsAs of May 23, 2025, 7 patients were enrolled: 5 women/2 men, median age 59y, 6 non-Hispanic White/1 Hispanic with unknown race. Tumor types included ovarian (n=3), pancreatic (n=2), non-small cell lung adenocarcinoma (NSCLC; n=1), and colorectal (n=1). A2B694 dose groups were 1×108 (n=3) and 2×108 (n=4) cells. Lymphodepletion was well-tolerated, with expected, transient cytopenias. All patients had ≥1 adverse event, most commonly chest pain (non-cardiac), fatigue, and neutropenia (each in 4 patients) and anemia, cough, decreased appetite (1 serious), leukopenia, and lymphopenia (each in 3 patients). One patient had Grade 3 ICANS and was treated with a prolonged course (41 days) of dexamethasone. There were no dose-limiting toxicities, cytokine release syndrome, or new safety signals after 9 months of follow-up.All 7 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood and in a tumor biopsy collected on Day (D) 42, demonstrating that A2B694 persists in the tumor microenvironment (figure 2). Six patients had progressive disease by D90. The patient with KRASG12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion and had a confirmed CR per RECIST 1.1 by central review at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease.ConclusionsA2B694 has manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. CR per RECIST 1.1 was observed in 1 patient with KRASG12V/STK11 co-mutated NSCLC. The maximum tolerated dose has not been reached and the dose-escalation phase to determine the RP2D continues.AcknowledgementsThe authors would like to thank the patients, their families, and their caregivers for participating in this trial; the screeners, clinical research coordinators, study nurses, data managers, and apheresis teams at each study site; and A2 Bio. Medical writing support was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA) and funded by A2 Bio.Trial RegistrationClinicalTrials.gov, NCT06051695ReferencesHecht J, et al. Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity. J Clin Oncol. 2022;40(suppl 4):190.Beatty GL, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology. 2018;155:29–32.Haas AR, et al. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol Ther. 2023;31:2309–2325.Hong D, et al. 959O Gavocabtagene autoleucel (gavo-cel, TC-210) dose escalation in refractory mesothelin-expressing solid tumors. Ann Oncol. 2021;32(suppl 5):S830.Hamburger AE, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.Punekar SR, et al. EVEREST-2: Initial data of the logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy A2B694 for patients with solid tumors associated with mesothelin (MSLN) expression and with human leukocyte antigen (HLA) loss of heterozygosity (LOH). J Clin Oncol. 2025;43(16 suppl):3040.Ethics ApprovalThis trial was approved by each site’s institutional review board.Abstract 535 Figure 1The structure of Tmod CAR T cells expressing a MSLN-targeted activator and an HAL-A*02-targeted blocker[Image Omitted. See PDF.]Abstract 535 Figure 2A2B694 levels over time[Image Omitted. See PDF.]

BackgroundDespite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated.1 While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy.2 A2B395 is an allogeneic, logic-gated, EGFR-targeted, Tmod CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells with preserved HLA expression, decreasing the risk for graft-vs-host disease (ie, on-target, off-tumor toxicity).3 To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response.4 Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy.5 A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (figure 1).MethodsDENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including colorectal, non-small cell lung, squamous cell head and neck, triple-negative breast, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of phase 1 is to evaluate safety, tolerability, and the recommended phase 2 dose using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm recommended phase 2 dose and collect biomarker data. Phase 2 will assess overall response rate per RECIST v1.1.ResultsThe first patient was enrolled on DENALI-1 in May 2025. Dose escalation is ongoing (figure 2).AcknowledgementsThe authors would like to thank the patients, their families, and their caregivers for participating in this trial; the screeners, clinical research coordinators, study nurses, data managers, and apheresis teams at each study site; and A2 Bio. Medical writing support was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA) and funded by A2 Bio.Trial RegistrationClinicalTrials.gov, NCT06682793ReferencesThe Cancer Genome Atlas (TCGA) Research Network. Accessed June 2021. https://www.cancer.gov/tcgaMacdonald JB, et al. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol. 2015;72(2):203–218.Hamburger AE, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.DiAndreth B, et al. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030.Grierson PM, et al. 588 EVEREST-1: initial safety data from a seamless phase 1/2 study of A2B530, a logic-gated Tmod CAR T-cell therapy, in patients with solid tumors associated with CEA expression also exhibiting HLA-LOH. J ImmunoTher Cancer. 2024;12(Suppl_2):A670-A671.Kirtane K, et al. Logic-gated, allogeneic Tmod chimeric antigen receptor T-cell (CAR T) therapy targeting epidermal growth factor receptor (EGFR) in advanced solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH): DENALI-1 trial. J Clin Oncol. 2025;43(16 suppl): TPS2677.Ethics ApprovalThis trial was approved by each site’s institutional review board.Abstract 585 Figure 1Logic-Gated CAR T With the Goal to Reduce Toxicity: MSLN (Activator) and HLA-A*02 (Blocker) [6][Image Omitted. See PDF.]Abstract 585 Figure 2DENALI 1 dose escalation study design[Image Omitted. See PDF.]