Tumor-infiltrating Lymphocytes Research Articles

IGSF3 tissue expression in squamous cell carcinoma of the oropharynx: a novel tool for prognosis assessment in HPV-related and HPV-unrelated disease.

Biomarkers are not broadly used in the management of head and neck cancers (HNCs). Biomarkers have been beneficial in the management of other cancers, however, not in HNCs. Therefore, we observed the immunopositivity of a novel biomarker called immunoglobulin superfamily member 3 (IGSF3) in tumor tissues in HPV-related and HPV-unrelated OPSCC. Two patient cohorts (C1 and C2) from separate time periods were available for this study (total N = 282). Both consisted of OPSCC patients treated at the Helsinki University Hospital (HUS, Helsinki, Finland) during 2000-2016. For HPV determination, HPV mRNA in situ hybridization was used. Immunohistochemistry was used to assess IGSF3 immunopositivity in cancer tissues. Overall survival (OS) was used as endpoint in the statistical analysis. In C1, stronger immunopositivity of IGSF3 in tumor-infiltrating lymphocytes (TILs) correlated with favorable OS (p = 0.005). Stronger IGSF3 immunopositivity in tumor cells (TCs) was associated with HPV negativity (p = 0.017). Stronger IGSF3 immunopositivity in TILs correlated with HPV positivity (p < 0.001). Elevated IGSF3 immunopositivity in TILs associates with HPV-related tumors and may signify favorable prognosis. The immunopositivity of IGSF3 differs between HPV-related and HPV-unrelated OPSCC.

Lifileucel: First Approval.

Lifileucel (AMTAGVI™), a one-time autologous T cell therapy derived and expanded from tumour-infiltrating lymphocytes (TIL) from a patient's own tumour, is being developed by Iovance Biotherapeutics, Inc. for the treatment of cancer. Lifileucel was granted accelerated approval based on objective response rate (ORR) in February 2024 in the USA for use in adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. This article summarizes the milestones in the development of lifileucel leading to this first approval for the treatment of patients with unresectable or metastatic melanoma who have progressed on or after prior anti-PD-1/L1 therapy and targeted therapy.

Lectin-like Transcript-1 (LLT1) Expression in Oral Squamous Cell Carcinomas: Prognostic Significance and Relationship with the Tumor Immune Microenvironment

Lectin-like transcript-1 (LLT1) expression is detected in different cancer types and is involved in immune evasion. The present study investigates the clinical relevance of tumoral and stromal LLT1 expression in oral squamous cell carcinoma (OSCC), and relationships with the immune infiltrate into the tumor immune microenvironment (TIME). Immunohistochemical analysis of LLT1 expression was performed in 124 OSCC specimens, together with PD-L1 expression and the infiltration of CD20+, CD4+, and CD8+ lymphocytes and CD68+ and CD163+-macrophages. Associations with clinicopathological variables, prognosis, and immune cell densities were further assessed. A total of 41 (33%) OSCC samples showed positive LLT1 staining in tumor cells and 55 (44%) positive LLT1 in tumor-infiltrating lymphocytes (TILs). Patients harboring tumor-intrinsic LLT1 expression exhibited poorer survival, suggesting an immunosuppressive role. Conversely, positive LLT1 expression in TILs was significantly associated with better disease-specific survival, and also an immune-active tumor microenvironment highly infiltrated by CD8+ T cells and M1/M2 macrophages. Furthermore, the combination of tumoral and stromal LLT1 was found to distinguish three prognostic categories (favorable, intermediate, and adverse; p = 0.029, Log-rank test). Together, these data demonstrate the prognostic relevance of tumoral and stromal LLT1 expression in OSCC, and its potential application to improve prognosis prediction and patient stratification.

Tumor-infiltrating lymphocytes: opportunities to use their potential in clinical practice in breast cancer

Introduction. Tumor-infiltrating lymphocytes are currently considered as a prognostic biomarker of cancer patient survival and response to therapy, as well as a target for immunotherapy. However, tumor-infiltrating lymphocytes are only part of the tumor microenvironment, which consists of cellular and cytokine components. The cellular component also includes tumor-associated macrophages, neutrophils, fibroblasts and other cells. The cytokine component is represented by the products of the activity of all cells of the microenvironment, as well as tumor cells. The purpose of this review is to consider various subpopulations of tumor-infiltrating lymphocytes, show their interaction with tumor cells and other cell populations of the tumor microenvironment, and also evaluate the possibilities of clinical use of this cell population as a biomarker using the example of breast cancer. Material and research methods. Materials for evaluating the importance of tumor-infiltrating lymphocytes as one of the components of the tumor microenvironment for clinical practice were publications in domestic and foreign journals over the past 5-7 years. Results. This review examines various subpopulations of tumor-infiltrating lymphocytes, shows their interaction with tumor cells and other cell populations of the tumor microenvironment, and also describes the potential for clinical use of this cell population as a biomarker for predicting clinical outcomes and the possibility of their use to determine the most effective treatment for cbreast cancer. Conclusion. Obtaining new data on the previously poorly studied components of the tumor microenvironment and tumor-infiltrating lymphocytes, as well as the formation of ideas about the mutual influence of tumor microenvironment cells and tumor cells open up the prospect of developing innovative models of therapy. One of the modern directions is the search for molecular mechanisms of maintaining the antitumor activity of tumor-infiltrating lymphocytes, as well as the polarization of cells in the tumor microenvironment. Advances in the field of molecular oncology will make it possible to reduce the mortality rate of cancer patients to minimal levels while maintaining or even improving their standard of living.

FOXO1 is a master regulator of memory programming in CAR T cells.

A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durableCAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated withpositive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

Histologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden.

Conjunctival squamous cell carcinoma (conjSCC) is more prevalent and aggressive in sub-Saharan African countries compared with the rest of the world. This study aims to compare the genomic, immunophenotypic, and histologic features between patients from the United States and Ethiopia, to identify etiopathogenic mechanisms and unveil potential treatment strategies. We compared histologic features and mutational profiles using whole exome sequencing, high-risk human papillomavirus (HPV) status, PD-L1 expression, and tumor-infiltrating lymphocytes in conjSCC tumors of patients from Ethiopia (ETH; n = 25) and the United States (from MD Anderson [the MDA cohort]; n = 29). Genomic alterations were compared with SCCs from other anatomic sites using data from The Cancer Genome Atlas. Solar elastosis was seen in 78% of ETH and 10% of MDA samples. Thicker tumors had higher density of CD8+ and CD3+ cells. HPV status was similar between the cohorts (ETH = 21% and MDA = 28%). The mean tumor mutation burden (TMB) was significantly higher in conjSCC (3.01/Mb, log10) and cutaneous SCC compared other SCC subtypes. ETH samples had higher TMB compared to the MDA cohort (3.34 vs. 2.73). Mutations in genes associated with ultraviolet light (UV) signature were most frequently encountered (SBS7b = 74% and SBS7a = 72%), with higher prevalence in the ETH cohort, whereas SBS2 and SBS13 signatures were more common among MDA HPV+ conjSCCs. Our findings suggest that UV exposure may play a major role in conjSCC, with a higher prevalence in the ETH cohort compared with the MDA cohort, where HPV also contributes.

Cimetidine repurposed as a potential immunomodulatory agent against colorectal carcinoma: A systematic review.

To determine the survival benefit and immunomodulatory effects of cimetidine pre-, peri- or post-operatively in patients with colorectal cancer (CRC). A systematic review was conducted using PubMed and Cochrane Library to retrieve randomized control trials (RCTs) that investigated the effects of cimetidine on survival and immunomodulation via improvement in tumor infiltrating lymphocytes (TILs) and peripheral blood lymphocytes. The review was carried out in accordance with the extended Preferred Reporting Items for Systematic Reviews and Meta-analyses. Four studies with the total of 267 patients were included in this systematic review. Treatment duration varied from 5 days to 1 year. Two studies reported a significant TIL response in the resected specimens after administering cimetidine, while one RCT showed an escalation of CD3, CD4 and CD57 lymphocytes in peripheral blood compared to the baseline following cimetidine treatment (p < 0.01). Of the three trials that examined the effects of cimetidine on survival, only two studies revealed significant survival benefit while the remaining study only showed a trend towards survival benefit. Repurposing of existing drugs like cimetidine has a potential to offer a survival benefit by acting as an immunomodulatory agent in patients undergoing curative resection for CRC. However, the heterogeneity seen in current studies and the evolvement of adjunctive therapies for CRC warrant large-scale, well-designed prospective RCTs to establish the efficacy of cimetidine in CRC.

Proteomics study of primary and recurrent adamantinomatous craniopharyngiomas

BackgroundAdamantinomatous craniopharyngiomas (ACPs) are rare benign epithelial tumours with high recurrence and poor prognosis. Biological differences between recurrent and primary ACPs that may be associated with disease recurrence and treatment have yet to be evaluated at the proteomic level. In this study, we aimed to determine the proteomic profiles of paired recurrent and primary ACP, gain biological insight into ACP recurrence, and identify potential targets for ACP treatment.MethodPatients with ACP (n = 15) or Rathke’s cleft cyst (RCC; n = 7) who underwent surgery at Sanbo Brain Hospital, Capital Medical University, Beijing, China and received pathological confirmation of ACP or RCC were enrolled in this study. We conducted a proteomic analysis to investigate the characteristics of primary ACP, paired recurrent ACP, and RCC. Western blotting was used to validate our proteomic results and assess the expression of key tumour-associated proteins in recurrent and primary ACPs. Flow cytometry was performed to evaluate the exhaustion of tumour-infiltrating lymphocytes (TILs) in primary and recurrent ACP tissue samples. Immunohistochemical staining for CD3 and PD-L1 was conducted to determine differences in T-cell infiltration and the expression of immunosuppressive molecules between paired primary and recurrent ACP samples.ResultsThe bioinformatics analysis showed that proteins differentially expressed between recurrent and primary ACPs were significantly associated with extracellular matrix organisation and interleukin signalling. Cathepsin K, which was upregulated in recurrent ACP compared with that in primary ACP, may play a role in ACP recurrence. High infiltration of T cells and exhaustion of TILs were revealed by the flow cytometry analysis of ACP.ConclusionsThis study provides a preliminary description of the proteomic differences between primary ACP, recurrent ACP, and RCC. Our findings serve as a resource for craniopharyngioma researchers and may ultimately expand existing knowledge of recurrent ACP and benefit clinical practice.

[Clinicopathological characteristics and immune microenvironment of breast squamous cell carcinoma].

Objective: To investigate the clinicopathological characteristics of breast squamous cell carcinoma and to analyze the relationship between its immune microenvironment tumor infiltrating lymphocytes (TILs) and prognosis. Methods: Forty-four cases of primary squamous cell carcinoma of the breast diagnosed and treated in the First Affiliated Hospital of Air Force Medical University, Xi'an, China from January 2006 to July 2022 were selected. Their clinicopathological characteristics were analyzed. The cell composition of TILs was evaluated using immunohistochemistry (Mainly markers of B lymphocytes, T lymphocytes and plasma cells). The relationship between TILs and prognosis was also analyzed. Results: The 44 patients of breast squamous cell carcinoma were all female and all were invasive carcinoma. Eight cases (8/44, 18.2%) were squamous cell carcinoma, while 36 cases (36/44, 81.8%) were mixed squamous cell carcinoma. The mixed components included non-specific carcinoma and spindle cell metaplastic carcinoma (17 cases each). One case contained ductal carcinoma in situ of the breast and 1 case contained tubular carcinoma. The proportion of squamous cell carcinoma was 10% to 90%. The cases with pure squamous cell carcinoma often had a large cystic cavity, which was lined by atypical squamous epithelium, while infiltrating squamous cell carcinoma nests were seen in the breast tissue around the cystic cavity. Immunohistochemical staining showed that p63 and CK5/6 were expressed in the squamous cell carcinoma component, but ER, PR and HER2 were not, except for one case of HER2 1+. The positive rates of TRPS1 and PDL-1 were 76% and less than 1%, respectively. Fifteen cases were in the high TILs group (TILs≥30%) and 29 cases were in the low TILs group (TILs<30%). Twenty-three patients were followed up for 5 to 118 months. Among them, 12 died within 3 years and 9 were alive at the end of the follow up. There was no significant difference in TNM stage, TILs and prognosis between simple squamous cell carcinoma and mixed squamous cell carcinoma. Conclusions: Breast squamous cell carcinoma can be divided into simple squamous cell carcinoma and mixed squamous cell carcinoma. There are differences in gross findings and histology between the simple and mixed squamous cell carcinoma of the breast. Sufficient samples should be taken to avoid missing the diagnosis of a minor squamous component. The prognosis of patients with high TILs is significantly better than that of patients with low TILs. The expression rate of TRPS1 in primary squamous cell carcinoma of breast is high and helpful to the differential diagnosis from metastatic squamous cell carcinoma.

Comparison of Microsatellite Instability With Clinicopathologic Data in Patients With Colon Adenocarcinoma.

Background Microsatellite instability (MSI) is a genetic condition caused by errors in DNA repair genes that cause colorectal cancer (CRC). The literature contradicts the frequency of MSI in sporadic CRCs and its effect on prognosis. This study investigated the distribution of clinicopathologic features and the relationship between MSI and survival outcomes. Methodology This is a retrospective study of 101 consecutive cases of CRC and immunohistochemical studies. All cases were retrospectively reviewed and reevaluated by histological grade, lymphovascular invasion, perineural invasion, tumor borders, dirty necrosis, tumor-infiltrating lymphocytes (TILs), Crohn's-like lymphoid reaction, mucinous and medullary differentiation, and tumoral budding from pathological slides. An immunohistochemical study was performed in appropriate blocks for using MLH-1, MSH-2, MSH-6, and PMS-2. We collected the clinical stage, pathological tumor stage, lymph node metastasis, age, sex, tumor diameter, distant metastasis, localization, and survival information from patients' clinical data. Results There was no statistically significant difference between the two groups regarding age, gender, tumor diameter, histological grade, tumor border, dirty necrosis, TILs, N and M stage, perineural and lymphovascular invasion, mucinous differentiation, medullary differentiation, and tumor budding characteristics of the patients. The MSI-H group was more frequently located in the right colon and transverse colon (p < 0.001), and the T stage was higher among them than in the MSI-L group (p = 0.014). Upon multivariate regression analysis, MSI status had no significant effect on survival time. Age and stage N and M were independent prognostic factors for colon cancer prognosis. Conclusions Our study presented the distribution of clinicopathological features and their relationship with MSI for 101 regional CRC patients. MSI status was detected by immunohistochemistry. Identifying MSI in CRCs may help personalize therapy planning. As the distribution of the features may vary from population to population, further investigations are needed on this topic.

Effect of Neoadjuvant Chemotherapy on Tumor-Infiltrating Lymphocytes in Resectable Gastric Cancer: Analysis from a Western Academic Center.

Tumor-infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles, as evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, as well as total TILs (CD4+, CD8+, Treg, B cells), within chemotherapy-treated tumors compared with chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic responses with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherapy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

Enhancement of antitumor response of staphylococcal enterotoxin C2 mutant 2M-118 by promoting cell-mediated antitumor immunity

BackgroundStaphylococcal enterotoxin C2 (SEC2) is used as an immunotherapeutic drug in China. However, SEC2 are limited due to its immunosuppressive and toxic effects. A SEC2 2M-118 (H118A/T20L/G22E) mutant generated by site-directed mutagenesis was studied to elucidate the underlying antitumor mechanism. MethodsThe effects of 2M-118 on mouse fibrosarcoma (Meth-A) cells and cytokine responses were tested in vitro using a transwell assay and ELISA, respectively. 2M-118 effect on immune function in tumor-bearing mice was tested. Cytokine levels and antitumor responses were measured using ELISA and flow cytometry, respectively. TUNEL staining and immunohistochemistry were employed to detect the tumor apoptosis and CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in tumor tissue. Results2M-118 demonstrated the growth inhibition on tumor cells, increase of cytokines production (IL-2, IFN-γ, and TNF-α) and splenocyte proliferation in vitro. 2M-118 effectively inhibited tumor development and increased lymphocytes and cytokines in a tumor-bearing mouse model. Additionally, 2M-118 regulated the tumormicroenvironment by reducing the number of myeloid-derived suppressor cells (MDSCs), increasing the number of TILs, and inducing tumorcell apoptosis. Conclusion2M-118 promotes immune function and enhances antitumor response. This indicates that 2M-118 could potentially be developed as a novel anti-tumor drug with-highefficiencyandlowtoxicity.

Abstract LB065: Tumor-infiltrating lymphocytes (TIL) engineered with regulatable membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14) show enhanced efficacy in fibroblast-containing cold tumors

Abstract Introduction: Adoptive cellular therapies (ACT) have encountered challenges in solid tumors due in part to the immunosuppressive tumor microenvironment (TME). We have developed OBX-115, TIL engineered to express mbIL15 regulatable using the cytoDRiVE® platform, which allows for TIL expansion, persistence, and anti-tumor efficacy under control of the FDA-approved small-molecule ligand, acetazolamide (ACZ), eliminating the need for co-administration of IL2 (NCT05470283). LIGHT, a tumor necrosis factor family member, interacts with lymphotoxin beta receptor (LTbR) and herpes virus entry mediator (HVEM) found on various TME cell types, including stromal cells such as cancer associated fibroblasts (CAF). In preclinical studies, LIGHT expression within a tumor has been linked to the formation of tertiary lymphoid structures and vascular normalization (Ramachandran Cancer Cell 2023), both associated with better clinical outcomes (Sautès-Fridman Nat Rev Cancer 2019). We hypothesized that engineering TIL with regulatable mbIL15 and LIGHT expression could enhance their efficacy by modifying the TME. Methods: TIL from colorectal (CRC) and head and neck squamous cell carcinoma (HNSCC) were transduced with retroviral vectors to express regulatable mbIL15 and LIGHT. ACZ-induced surface expression of mbIL15 and LIGHT in expanded TIL was examined using flow cytometry. Functional signaling of LIGHT was assessed through co-culture with Jurkat-HVEM-NF-kappaB reporter cells and LTbR+ HUVEC cells. In vitro, engineered TIL were tested in stromal-rich tumor models (CRC and HNSCC) by co-culturing with autologous patient-derived tumor/CAF hybrid spheroids. In vivo, antigen-independent TIL persistence was assessed in NSG mice without exogenous IL2. Syngeneic studies were performed to assess the efficacy of adoptively transferred mbIL15 and LIGHT-engineered Pmel cells (CD8+ T cells transgenic for a gp100-specific T cell receptor) in a subcutaneous cold tumor model (B16-F10). Results: Engineered TIL were successfully expanded without exogenous IL2. ACZ-dependent mbIL15 and LIGHT expression were confirmed, validating co-regulation and functionality in vitro. TIL engineered with mbIL15 and LIGHT displayed significantly increased cytotoxicity against autologous tumor/CAF spheroids compared with TIL expressing mbIL15 alone (p&amp;lt;0.005) in CRC and HNSCC tumor/CAF hybrid models. TIL with mbIL15 and LIGHT expanded in vivo and persisted for ≥42 days without exogenous IL2 support. Moreover, Pmel cells engineered with mbIL15 and LIGHT demonstrated durable anti-tumor efficacy in B16-F10 tumor-bearing mice, which was greater than Pmel cells engineered with mbIL15 alone (p&amp;lt;0.01). Conclusions: These preclinical results suggest that TIL engineered with regulatable mbIL15 and LIGHT using the cytoDRiVE platform have the potential to address the high unmet clinical need in cold tumors with suppressive TME, which are currently not amenable to ACT. Citation Format: Balazs Koscso, Zheng Ao, Carmela Passaro, Nirzari Shah, Ngoc Ly, Patricia Timpug, Bulent A. Aksoy, Dexue Sun, Dan Jun Li, Kerri-Lynn Sheahan, Violet Young, Theresa Ross, Benjamin Primack, Meghan Langley, Jeremy Tchaicha, Dhruv K. Sethi, Jan ter Meulen, Michelle Ols. Tumor-infiltrating lymphocytes (TIL) engineered with regulatable membrane-bound IL15 (mbIL15) and LIGHT (TNFSF14) show enhanced efficacy in fibroblast-containing cold tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB065.

Abstract CT012: PARTNER Trial: Neoadjuvant olaparib in triple negative breast cancer (TNBC)

Abstract Background: TNBCs in patients (pts) who are germline BRCA wild type (gBRCAwt) may show homologous recombination deficiency and genomic instability, resulting in a BRCA-like phenotype. The PARTNER Trial tested olaparib in combination with neoadjuvant carboplatin and paclitaxel in pts with TNBC (gBRCAwt). Methods: Pts with TNBC diagnosed locally were confirmed centrally with immunohistochemistry for ER, PR, HER2 and EGFR, CK5/6 and AR to define basal-like TNBC, before entry to the PARTNER trial. Pts were gBRCAwt. Tumours were assessed for tumour infiltrating lymphocytes (TILs). Pts were randomised 1:1 to research (R) and control arms (C). Pts received neoadjuvant carboplatin AUC 5, day(d) 1, with paclitaxel 80mg/m2 d1, 8, 15, every (q) 3 weeks (w), x 4 cycles(cy), +/- olaparib 150mg bd, po, d3-14 q 3w. Then all pts had 3cy of anthracycline chemotherapy before surgery. Primary endpoint was pathological complete response (pCR), and secondary endpoints included event-free survival (EFS), and overall survival (OS). A total of 454 patients were needed to attest 90% power with 5% significance assuming pCR rate of 50% in C and 65% in R. Results: From Sept 2016 to Dec 2021, 559 pts with TNBC (gBRCAwt) were randomised at 29 UK centres. Data cut-off was 30/11/23 with median (med) follow-up of 38 months (m). There were 276 R and 264 C pts in the intention-to-treat population. Pt and tumour characteristics were balanced between the arms: med pt age 49 years; 95% ECOG 0; 36% previous oophorectomy or post-menopausal; 95% tumour size ≤50mm; TILS score ≥60% in 22%. In R, 88% received at least 80% of the planned olaparib dose. More than 90% of patients in both R and C received at least 80% of the planned carboplatin (R 96% and C 94%) and paclitaxel (R 100% and C 99%) doses.Of 543 pts, 141 (51.1%) in R and 140 (52.4%) in C had a pCR with a difference of -1.3% (95% CI -9.7% to 7.0%, p-value=0.753). Percentage of pts with pCR increased with increasing TILs; pCR rate was 32% with TILs 0-10%, increasing to 67% with TILs 90-100%. Estimated EFS at 36 months (m) was 80% in R and 79% in C (log-rank p&amp;gt;0.9); estimated OS at 36m was 90% in R and 87.2% in C (log-rank p=0.8). Estimated 36m EFS rate was 90.4% (95% CI, 86.4 to 94.5) in pts with pCR and 70% (95% CI, 64.2 to 76.2) in pts with non-pCR (HR=0.3, 95% CI 0.2 to 0.4; p &amp;lt; 0.001). Estimated 36m OS was 95.7% (95% CI, 93.0 to 98.5) in pts with pCR, and 83% (95% CI, 78 to 88.2) in pts with non-pCR (HR=0.2, 95% CI 0.1 to 0.3; p &amp;lt; 0.001). More events and deaths were observed in non-pCR pts compared to pCR pts regardless of the treatment received. Conclusions: Neo-adjuvant olaparib in the dose and schedule tested, in addition to carboplatin/taxol and anthracycline chemotherapy in basal-like TNBC in gBRCAwt patients, did not improve pCR rates, EFS or OS. Pts who achieved a pCR had significantly better EFS and OS than those with non-pCR. These results are in marked contrast to the significant benefit of olaparib in those with gBRCA mutations reported in parallel. Citation Format: Jean E. Abraham, Karen Pinilla, Louise Grybowicz, Alimu Dayimu, Nikolaos Demiris, Caron Harvey, Lynsey M. Drewett, Rebecca Lucey, Alexander Fulton, Anne N. Roberts, Joanna R. Worley, Anita Chhabra, Wendi Qian, Richard M. Hardy, Stephen Chan, Tamas Hickish, Devashish Tripathi, Ramachandran Venkitaraman, Mojca Persic, Shahzeena Aslam, Daniel Glassman, Sanjay Raj, Annabel Borley, Jeremy P. Braybrooke, Stephanie Sutherland, Emma Staples, Lucy C. Scott, Mark Davies, Cheryl A. Palmer, Margaret Moody, Mark J. Churn, Jacqueline C. Newby, Mukesh B. Mukesh, Amitabha Chakrabarti, Rebecca R. Roylance, Philip C. Schouten, Nicola Levitt, Karen McAdam, Anne C. Armstrong, Ellen R. Copson, Emma McMurtry, Marc Tischkowitz, Elena Provenzano, Helena Earl, PARTNER Trial Group. PARTNER Trial: Neoadjuvant olaparib in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT012.

Abstract LB072: Tumor-infiltrating lymphocytes (TIL) engineered with membrane-bound IL15 (cytoTIL15 cells) exhibit pharmacologically regulatable signal transduction in cis and trans

Abstract Introduction: We have previously shown the successful engineering of membrane-bound IL15 (mbIL15)-expressing tumor-infiltrating lymphocytes (TIL; cytoTIL15™ cells) from solid tumors such as melanoma, which are CD8+ enriched TIL exhibiting enhanced persistence and anti-tumor activity compared with unengineered TIL (SITC 2022, 2023; clinical candidate OBX-115: NCT05470283). The mbIL15 expressed by cytoTIL15 cells is regulated via a carbonic anhydrase 2 (CA2) drug-responsive domain, which allows expression to be induced upon delivery of the FDA-approved small molecule ligand acetazolamide (ACZ) and was designed to engage the IL2Rβ and IL2Rγ receptors in both cis and in trans. Using natural killer (NK) cells, which are potently responsive to soluble, trans-presented IL15, as an experimental model system, we examined the potential of mbIL15 on cytoTIL15 cells to potentiate activity in both cis and trans. Methods: cytoTIL15 cells and unengineered TIL were generated as described previously (SITC 2022, 2023). Cells were assessed for expression of mbIL15 and phosphorylation of downstream signaling molecules STAT5 and S6 by flow cytometry, and co-cultured with allogeneic healthy donor NK cells for 1-10 days with and without transwell inserts. Functional effects of cytoTIL15 cells were compared to those of soluble recombinant IL15. Supernatant was obtained from co-cultures for assessment of cytokine production. Results: cytoTIL15 cells demonstrated robust ACZ-dependent mbIL15 expression, and ACZ dosing regulated mbIL15 activity in cis by potentiating the phosphorylation of STAT5 (geoMFI with 0 vs. 25 µM ACZ, p=0.012) and S6 (geoMFI with 0 vs. 25 µM ACZ, p=0.016). Upon removal of ACZ, mbIL15 expression and pSTAT5 and pS6 returned to basal levels within 24 hours. mbIL15 expressed on the surface of cytoTIL15 cells could also activate cells in trans in an ACZ-dependent titratable manner. Specifically, co-culture of cytoTIL15 cells with NK cells led to an ACZ-dependent increase in pSTAT5 (geoMFI with 0 vs. 25 µM ACZ, p=0.038) in NK cells, which was not seen in co-cultures of unengineered TIL with NK cells. Additionally, NK cells showed a similar cytokine production profile when exposed to mbIL15 by cytoTIL15 cells as with soluble, trans-presented IL15. NK cell transactivation relied on direct cell contact with cytoTIL15 cells, as magnitudes of phosphorylation were decreased in co-cultures with NK and cytoTIL15 cells separated by a transwell membrane (pSTAT5 geoMFI p=0.008). Conclusions: cytoTIL15 cells demonstrate functional engagement of cytokine receptors via mbIL15 in both cis and in trans, including phosphorylation of STAT5 and S6. Taken together, these data highlight the potential for robust activity of cytoTIL15 cells through potentiation of ACZ-dependent mbIL15 activity in both cis and trans. Citation Format: Rachel Burga, Gauri Kulkarni, Zheng Ao, Dhruv K. Sethi, Jan ter Meulen, Michelle Ols. Tumor-infiltrating lymphocytes (TIL) engineered with membrane-bound IL15 (cytoTIL15 cells) exhibit pharmacologically regulatable signal transduction in cis and trans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB072.

Abstract CT285: Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma

Abstract Introduction ICI have improved outcomes for pts with melanoma; however, most pts (~60%) do not achieve long-term survival. Unengineered bulk TIL cell therapy has an objective response rate (ORR) of 31-49% in pts with unresectable or metastatic melanoma (Rohaan NEJM 2022, Chesney JITC 2022), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express regulatable membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is currently enrolling. The current study (NCT06060613) is enrolling at multiple US sites using centralized manufacturing. Methods 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 pts with unresectable or metastatic melanoma resistant to ICI (Table). Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of the OBX-115 regimen; Phase 2 will evaluate efficacy (ORR using RECIST v1.1). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core biopsy, and is infused after standard- or low-dose (based on clinical eligibility) lymphodepletion (cyclophosphamide and fludarabine). ACZ is administered at cohort-defined doses once daily for up to 10 days, with ACZ redosing at Week 6-8 for 10 days if the initial observed tumor response is less than partial response. No systemic high-dose IL2 is administered. Two sites are open and recruiting pts. TABLE 1. NAND Key Eligibility Criteria Key Inclusion Criteria Key Exclusion Criteria Age ≥18 years Uveal melanoma Histologically confirmed diagnosis of unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma Brain metastasis or leptomeningeal disease Documented radiographic disease progression after systemic therapy containing a PD-1- or PD-L1-blocking antibody (if adjuvant setting, progression during or within 12 weeks after the last dose) Active autoimmune disease, including active uveitis or any other medical illness that would pose increased risks for study participation Received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive Prior allogeneic organ transplant, allogeneic cell therapy, or genetically engineered cell therapy (not including autologous stem cell or unengineered TIL cell therapy) ≥1 lesion suitable for OBX-115 generation with expected minimum of 1.5-cm diameter; minimally invasive tumor tissue procurement (core biopsy) may be considered on a case-by-case basis after discussion with the Medical Monitor Systemic steroid therapy &amp;gt;10 mg/day of prednisone or equivalent ≥1 RECIST 1.1-measurable lesion remaining after tumor tissue procurement ECOG performance status 0 or 1 Estimated life expectancy &amp;gt;6 months Citation Format: Sajeve S. Thomas, Jason A. Chesney, Omid Hamid, Gino K. In, Alexander N. Shoushtari, Yazan Samhouri, Parameswaran Hari, Giridharan Ramsingh, Prakash Prabhakar, Lauren Mclaughlin, Allison Betof Warner. Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT285.

Abstract CT286: TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma

Abstract Introduction: Novel early-line therapies for advanced (unresectable or metastatic) melanoma are needed to improve the rate of deep and durable responses and increase the proportion of patients with long-term benefit. TILVANCE-301 will evaluate the efficacy and safety of lifileucel autologous TIL cell therapy plus pembrolizumab in patients with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group study that will randomize ~670 patients (1:1; Day 0) to Arm A: lifileucel plus pembrolizumab (Day 3: tumor tissue resection for TIL manufacturing; Day 5: pembrolizumab 200 mg; Day 26: pembrolizumab 400 mg; Day 28-29: cyclophosphamide 60 mg/kg; Day 28-32: fludarabine 25 mg/m2; Day 33: lifileucel; Day 34-37: ≤6 doses of high-dose IL-2; Week 10: pembrolizumab 400 mg Q6W) or Arm B: pembrolizumab alone (same pembrolizumab dosing as Arm A). Patients in Arm B with confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel monotherapy as immediate next treatment and may continue pembrolizumab until start of nonmyeloablative lymphodepletion. Eligible adults have histologically confirmed advanced melanoma, Eastern Cooperative Oncology Group performance status of 0-1, estimated life expectancy &amp;gt;6 months, ≥1 resectable lesion to generate lifileucel, and ≥1 remaining measurable lesion. Prior neoadjuvant or adjuvant treatment including immune checkpoint inhibitors may be allowed. Prior therapy for metastatic disease, symptomatic untreated brain metastases, organ allograft or prior cell therapy, uveal/ocular melanoma, and chronic systemic steroid therapy are not permitted. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) objective response rate (ORR) and progression-free survival (PFS). Key secondary efficacy endpoint is overall survival. Additional secondary efficacy endpoints include BIRC-assessed complete response (CR) rate, duration of response (DOR), and event-free survival (EFS); investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of treatment-emergent adverse events and relationship to study drug. Exploratory endpoints include in vivo T-cell persistence (unique CDR3 sequences in peripheral blood mononuclear cell [PBMC] over time) and correlative biomarkers (eg, lifileucel phenotypic and functional characteristics; lifileucel, tumor, and PBMC gene expression profiles; tumor mutational landscape). The study will enroll globally, with initial sites in Europe, North America, and Australia. Trial registration: NCT05727904 Citation Format: Sajeve Thomas, Young Ki Hong, Yazan Samhouri, James Larkin, David J. Olson, Gino K. In, Victoria Atkinson, Philip Lammers, Andrew J. Furness, Juan Martin-Liberal, Patrick Terheyden, Andrew S. Poklepovic, Ryan H. Nguyen, Idit Peretz, Marcus Butler, Adnan Khattak, Lavinia Spain, E.M. Gaughan, Melissa Wilson, John W. Dubay, Anja Williams, Stephanie Goff, Gary C. Doolittle, Jason Chesney, Friedrich Graf Finckenstein, Jeffrey Chou, Xiao Wu, Giri Sulur, Wen Shi, John Haanen. TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT286.

Abstract CT176: OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma

Abstract Introduction: Treatment options are limited for pts with ICI-resistant metastatic melanoma. Investigational unengineered TIL cell therapy has shown promising activity in this setting, but co-administration of systemic high-dose IL2 limits pt eligibility and is associated with safety risks. OBX-115 is an investigational, autologous TIL cell therapy engineered to express membrane-bound IL15 (mbIL15) under pharmacologic regulation by the FDA-approved small-molecule drug acetazolamide (ACZ) using cytoDRiVE® technology, to induce cytokine-driven TIL expansion and persistence without co-administration of IL2. Methods: This Phase 1 first-in-human study (NCT05470283) is assessing the safety, tolerability, and efficacy of the OBX-115 regimen in pts with unresectable or metastatic melanoma progressing after ICI. Initial pts are enrolled into dose-escalation cohorts (n=3 each; maximum doses: Cohort 1 [C1], 30 × 109 cells + ACZ 125 mg; Cohort 2b [C2b], 100 × 109 cells + ACZ 125 mg). OBX-115 is manufactured using the pt’s tumor tissue (procured by surgical excision or core needle biopsy) and infused after completion of cyclophosphamide and fludarabine lymphodepletion. ACZ is administered orally once daily for up to 7 days, with redosing (Week 6, up to 7 days) permitted for pts without radiographic response at Week 6. No systemic IL2 is administered. The primary objective is to evaluate safety (dose-limiting toxicities [DLTs] and treatment-emergent adverse events [TEAEs]). Results: As of 1 December 2023, 6 pts (age, 28-64 y; C1, n=3; C2b, n=3) with ICI-resistant metastatic melanoma completed the DLT-evaluation period. Median lines of prior therapy was 2.5 (range, 1-5). OBX-115 was successfully manufactured for all 6 pts, including from core needle biopsy tumor tissue (n=5). At 20 weeks median study follow-up (range, 11-51 weeks), no DLTs were observed; 3 pts experienced Gr 3 nonhematologic TEAEs (abdominal pain, ALT elevation, hypokalemia, hyponatremia, syncope) and no Gr 4 nonhematologic TEAEs were reported. Four pts received and tolerated ACZ redosing. ORR per RECIST 1.1 was 50% (2 CR, 1 PR, 3 SD); responses were established between Week 6-18 and ongoing at the time of data cut. All pts had consistent reduction of lesions at each assessment through Week 18. One pt developed new metastatic disease (liver) and progressed at Week 24, despite continued target lesion reduction. Updated data will be presented. Conclusions: OBX-115, a one-time, IL2-free, regulatable, engineered TIL cell therapy, was well-tolerated and induced consistently deepening and durable responses, with the potential to fulfill the unmet need in ICI-resistant advanced melanoma. These early results support continued investigation of the OBX-115 regimen in this and an ongoing Phase 1/2 multicenter study (NCT06060613). Citation Format: Rodabe N. Amaria, Jennifer L. McQuade, Michael A. Davies, Isabella C. Glitza Oliva, Steffy Jose, Erik N. Cressman, Ashlynd L. Clausell, Roland Bassett, Sapna Patel, Adi Diab, Hussein A. Tawbi, Michael K. Wong, Alexandra P. Ikeguchi, Madan Jagasia, Giridharan Ramsingh, Prakash Prabhakar, Raina Duan, Parameswaran Hari. OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT176.

Abstract LB445: USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein

Abstract Persistent programmed cell death-1 (PD-1)/PD-L1 inhibitory signaling disrupts T cell cytotoxic function, leading to T cell exhaustion—a phenomenon strongly associated with advanced cancer progression and immunotherapy failure. Deciphering the mechanisms behind dysregulated PD-1 expression and reactivating tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) is crucial. Our previous research established that tumor-associated macrophage-derived IL-6 promotes STAT3-dependent PD-1 transcriptional activity and immunotherapy resistance. The current study further explores whether IL-6 abundance in the TME contributes to PD-1 protein stability. Results indicate that IL-6 extended PD-1 protein half-life in T cells, suggesting its role in modulating PD-1 protein stability. Furthermore, analysis of the GEO database showed a positive correlation between the expression of ubiquitin-specific-processing protease (USP) family enzymes and PD-1 in non-responding patients receiving anti-PD-1 therapy. Knockdown experiments revealed that USP24 strongly downregulated PD-1 protein expression and stability. USP24 depletion reversed IL-6-induced PD-1 expression and stability, with USP24 colocalizing with PD-1 at the plasma membrane upon IL-6 stimulation. Immunoprecipitation-Western blot assays confirmed that USP24 directly interacted with PD-1 and countered E3 ligase c-Cbl-mediated ubiquitination. Depleting USP24 suppressed PD-1-mediated immunosuppression both in vitro and in vivo. In lung-specific EGFRL858R/USP24C1698A functional knockout mice, tumor progression was slower, and exhausted tumor-infiltrating PD-1+ TIM-3+ CD8+ T cells reduced compared to EGFRL858R mice. Inhibiting PD-1 stability with an IL-6 neutralizing antibody or the novel inhibitor USP24-i-101 decreased tumor volume and increased activated cytotoxic T cell infiltration in vivo. Moreover, USP24-i-101 enhanced therapeutic effects in combination with anti-CTLA4 immunotherapy. Clinically, our in-house cohort revealed elevated USP24 expression in tumor-infiltrating lymphocytes or peripheral T cells, correlating with worse clinical outcomes and unfavorable responses to immunotherapy in lung cancer patients. This study uncovers USP24 as a novel PD-1 regulator, deubiquitinating PD-1 to enhance protein stability and suppress T cell function. In conclusion, USP24 emerges as a potential target for enhancing anti-tumor immunity and as a biomarker predicting clinical responses to immunotherapy in lung cancer. Citation Format: Hung-Chia Hsieh, Jan-Jong Hung, Yi-Ching Wang. USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB445.

Abstract LB119: The immune-modulation of HM16390, firing up the poor tumor microenvironment to induce a potent anti-tumor efficacy

Abstract Immunotherapy, encompassing immune checkpoint blockades (ICBs) and immune stimulators, has become a widespread approach in cancer treatment. However, the effectiveness of these strategies relies significantly on the characteristics of the current tumor microenvironment (TME). This reliance underscores the urgent need for a potent immune modulator capable of inducing a favorable TME, particularly in non-immunogenic cold tumors. Here, we demonstrate that HM16390, a long acting IL-2 analog, has the potential to modify the immunogenicity of the TME by activating, expanding, and recruiting cytotoxic effector cells in cold tumor. In the murine B16F10 melanoma model, following the early upregulated proliferative potential, the proportions of CD8+ T as well as NK cells increased in both blood and tumor. While NK cell frequency initially increased and then recovered, CD8 T cells exhibited a dose-dependent upregulation in the late phase in both blood and tumor. Given the IL-2Rα (CD25) affinity of HM16390, there was an increase in Treg proportions in blood; however, intriguingly, Treg frequency decreased in the tumor. This pattern emphasizes the crucial role of HM16390 in balancing the hyper-activation of peripheral effector cells while simultaneously inducing a profoundly immune-favorable TME. Effector functions were also upregulated in both blood and tumor. Early upregulation of IFN-γ and TNF occurred in both blood and tumor, but the upregulation of granzyme B displayed a sustained expression pattern in the tumor. These immune-modulated features correlated with the exposures of HM16390, particularly noting a negative correlation between Treg down-regulation and Its exposure in blood. The immune modulations of HM16390 were validated in terms of efficacy in the Pancreatic Ductal Adenocarcinoma (PDAC) model. HM16390 was administered subcutaneously to panc02 tumor syngeneic mice via once-a-week administration for 6 weeks, with or without PD-1 combination treatment. HM16390 treatment group was well-tolerated and resulted in a dose-dependent anti-tumor effect. Notably, all mice treated with the highest dose exhibited a complete response. Furthermore, in panc02 syngeneic mice, known for a poor response to ICBs, the combination treatment of HM16390 with mAnti-PD-1 demonstrated synergistic anti-tumor effects. In conclusion, HM16390 demonstrates improved expansion and functions of effector tumor-infiltrating lymphocytes (TILs), correlating with exposure, and exhibits a safe Treg modulation pattern. These modulations culminate in a significant anti-tumor effect and synergies with PD-1 blockade in the B16F10 and PDAC model. Given that both B16F10 melanoma and Panc02 PDAC are recognized as poor immunogenic murine models with low TIL frequency, HM16390 shows promise in modifying the immunogenicity of the TME, thereby activating proper immune responses in preclinical models. Citation Format: Seongju Jeong, Yunjae Kim, Jooyun Byun, Jinyoung Kim, Jaehyuk Choi, Sungmin Bae, Daejin Kim, In Young Choi. The immune-modulation of HM16390, firing up the poor tumor microenvironment to induce a potent anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB119.