Background: CADI-05, a TLR-2 agonist, induces Th1 immune response following intradermal administration and has been found useful in management of lung cancer and melanoma. Objective: To evaluate CADI-05 in patients with BCG recurrent and unresponsive Non-muscle invasive bladder cancer (NMIBC) for 15-months recurrence free survival (RFS) rate. Methods: In BCG unresponsive (BU) or recurrent (BR) NMIBC, CADI-05 was administered intradermally every two weeks for 3 months followed by every month for 3 months and subsequently every 2 months for 6 months following transurethral resection (TUR) in a single arm study (ClinicalTrials.gov: NCT00694798). Cystoscopy, cytology, and sonography were performed for the presence/recurrence of NMIBC at 3, 6, 9, 12, 15 months and beyond and confirmed by biopsy. Evaluation of preoperative biopsy for Desmocollin-3 (DSC3) expression and tumor infiltrating lymphocytes (TIL) was optional. -Commercial License (CC BY-NC 4.0). 172 M. Results: Twenty patients with NMIBC received intradermal CADI-05. RFS at 15 and 30 months was 35% (7/20) patients. The median RFS was also better for BU compared to BR group (HR, 0.329; 95% CI, 0.071 to 1.532). DSC3 expression was present in 68.8% (11/16) patients. TIL and RFS beyond 30 months were seen 2.3 times and 2.8 times more often in DSC3 expressing NMIBC respectively. No grade IV or V adverse events occurred. Local site reactions were the most common adverse event. Conclusion: Intradermal CADI-05 following TUR is associated with 35% RFS at 30 months.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with an overall 5-year survival rate of <10% due to late stage diagnosis and poor clinical outcome with existing therapies. PDAC displays a high degree of tumor heterogeneity and immunosuppressive tumor microenvironment with lower tumor infiltrating lymphocytes (TIL). These factors contribute to resistance against chemotherapies and immunotherapies. Immunotherapies have shown activities across different tumor types including chemotherapy or targeted therapy resistant cancers however these options have little efficacy in the PDAC tumor. Here, in this study we tested the efficacy of gemcitabine in combination with Cadi-05 (TLR2 agonist) against established murine PDAC tumor models (Pan02 in C57/BL6 and 688M in B6129SF1/J). Animals were randomized to receive gemcitabine, Cadi-05, their combination or no treatment when they had tumor size ≈ 50 mm3, 65mm3 and 100 mm3. The weekly treatment of gemcitabine, Cadi-05 and their combination inhibited the tumor progression across all tumor sizes. At the end of study, PBMC and tumors were collected and analyzed for different immune parameters. Results revealed that Cadi-05 treatment alone was associated with increase in CD4+ and CD8+ T cells in PBMC as well as amongst TIL with significant decrease in their expression of immunosuppressive markers like FOXP3 and PD-1. Its combination with gemcitabine synergized the effect of each other. There was further increase in absolute TIL as well as TIL expressing CD4+ and CD8+ markers with decrease in FOXP3 and PD-1 expressing CD4+ and CD8+ TIL. Inhibition of tumor progression was associated with improved effector function of PBMC. Synergy between Cadi-05 and gemcitabine was also evident in effector function. In presence of established tumor, TLR2 agonist Cadi-05 improves effector function, increases CD4+ and CD8+ expressing TIL, decreases immune suppressive TIL and retards tumor growth. Our study suggests that combination of gemcitabine and Cadi-05 inhibits the tumor growth irrespective of its size and it is coupled with increased anti-tumor response and decreased immunosuppressive function Citation Format: Arpit Dheeraj, Chandreshwar Shukla, Dhanir Tailor, Nayan K. Jain, Kirsten Stefan, Chintan D. Patel, Rajiv Modi, Bakulesh M. Khamar, Sanjay V. Malhotra. TLR2 agonist as a novel therapeutic approach to treat pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4232.

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Introduction: Adhesion molecules are important for tissue integrity, its maintenance as well as communication (signaling). Desmocollin-3 (DSC3) one of the desmosomal adhesion (Desmoglein 1, 2, 3 and Desmocollin 1, 2, 3) proteins is a trans-membrane glycoprotein present in basal/suprabasal layer of normal stratified epithelium. It is a p53-responsive desmosomal cadherin protein. Cancer development and progression are associated with either additional cytoplasmic expression of DSC3 as seen with squamous non-small cell lung cancer and colorectal cancer or loss of DSC3 expression as seen in prostate and breast cancer To investigate the role of DSC3 in bladder cancer, we evaluated the expression levels of DSC3 in biopsy samples of patients with non-muscle invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma (MIBC) and correlated it with the clinical staging and immune cell infiltration. Also, its relationship with immune signature genes and immune cell subsets is evaluated using TCGA dataset available on c-bioportal. Materials and Method: DSC3 protein expression was evaluated by Immunohistochemistry. H&E stained slides were evaluated by light microscopy to identify immune cells as macrophages or lymphocytes and their location as intrastromal or intratumoral as previously described. It was correlated with the type, stage, and grade of the tumor. Spearman correlation between DSC3 and 207 immune signature genes available in TCGA data was calculated using RSEM and methylation values of each gene. Results: The data suggests that NMIBC is more likely to be DSC3 positive than MIBC. DSC3-positive samples are more likely to have tumor-infiltrating immune cells (TIL) compared to DSC3-negative samples. In silico analysis of bladder cancer shows that DSC3 mRNA expression is inversely proportional to its methylation. We found that DSC3 expression is biased towards the Th1 subset of immune cells. DSC3 is not correlated with PD-1/PDL1 expression, and the macrophage subsets are negatively correlated with DSC3. Conclusion: DSC3 expression is associated with the Basal/Squamous type of bladder cancer. Therefore, this study suggests the potential of DSC3 as a predictive biomarker for response to systemic immunotherapy and resistance/poor response to conventional therapy (chemotherapy; radiotherapy, and cystectomy) and underscores the need for studies evaluating the potential of DSC3 expression as a biomarker. Citation Format: Chandreshwar P. Shukla, Nayan K. Jain, Michael A. O'Donnell, Kapil J. Vachhani, Rashmi Patel, Aruna Vanikar, Rajiv I. Modi, Sanjay V. Malhotra, Bakulesh Khamar. Investigating the role of Desmocollin-3 and immune infiltrate in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5265.