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Immune check point inhibitor(s) have become a main stay of treatment for melanoma regardless of its mutational status. However, not all patients respond to treatment. In fact, only 40-60% respond to treatment. Currently, only PD-L1/PD-1 expression and mutational burden can predict response to treatment. Published data have shown that exosomal PD-L1 is an important factor contributing to response/failure to checkpoint inhibitor treatment. Exosome is known to carry several types of cargoes and is one of the important delivery systems in the body. We have begun to examine the role of exosomal PD-L1, PD-1 in predicting response, and as well as how to overcome drug resistance. We initiated an institutional study in metastatic melanoma patients who underwent immunotherapy treatment (anti-PD-1 + anti-CTLA 4 drugs). Blood samples were obtained at baseline and at subsequent treatment. Both serum and plasma exosomes were isolated. Eighteen patients were entered in the study. We have found that 1) Patients with PD-L1 negative tumor can have high exosomal PD-L1 expression, 2) all patients had exosomal PD-L1, and 3) all patients with decreased exosomal PD-L1 expression after treatment showed antitumor response [partial response (PR) or complete response (CR)]. In contrast, patients who had consistently high exosomal PD-L1 expression post-treatment showed no response, and this can be seen after the third cycle of treatment. Patients who achieved CR showed low exosomal PD-L1 and no exosomal PD-1 post-treatment. Importantly, we have also found that exosomes carry antiapoptotic protein and proapoptotic protein, as well as ATG family protein, which is related to autophagy. Whether these proteins also play a role in determining the cell fate in the metastatic sites is not known and will need future investigation. Interestingly, the two patients who showed no response also had high p-AKT. Since traditional anti PD-1 and anti-PD-L1 drugs do not have effect on exosomal PD-L1 and PD-1, we formed a collaboration with Dr. Stephane Roche at Florida Atlantic University, who has designed novel peptides by exploiting the innate plasticity of the PD-1 receptor (pembrolizumab H3 loop mimics). Thus far, we have screened many compounds and have selected 2 compounds for further testing. Together, we have also designed new PD-L1 peptides that can inhibit both PD-L1 and PI3K/AKT pathways simultaneously. Hence one can overcome checkpoint inhibitor resistance due to exosomal PD-L1/PD-1. Supported by grant from Sylvester Comprehensive Cancer Center and R21GM132754. Citation Format: Pablo Eduardo Puente, Dan Nguyen, Niramol Savaraj, Chunjing Wu, Medhi Wangpaichitr, Stephane Roche, Guangkuan Zhao, Alexis Richaud, Jose Lutzky, Leonel Hernandez Aya, Mecker Moller, Jessica Crystal, Neha Goel, Lynn Feun. Can exosomal cargoes predict checkpoint inhibitor response in melanoma, and can we overcome drug resistance. [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 4114.

We discovered a crucial change common to all platinum resistant (CR) NSCLC cells, wherein a high level of reactive oxygen species (ROS) modulates tumor metabolism. CR cells activate the kynurenine (KYN) pathway (KP) during excessive oxidative stress to maintain high ROS for proliferation by catabolizing tryptophan (TRP) to KYN via indoleamine 2,3-dioxygenase-1 (IDO1); and by expressing (3-5x) higher levels of programmed death-ligand 1 (PD-L1) compared to platinum sensitive cells (p Citation Format: Sydney Spector, Chunjing Wu, Dan Nguyen, George Theodore, Ashley Garcia, Lynn Feun, Niramol Savaraj, Medhi Wangpaichitr. Targeting kynurenine pathway using novel IDO/TDO dual inhibitor (AT0174) to modulate tumor microenvironment in platinum resistant non-small cell lung cancer cancer: An immunometabolism compliment markers [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 2325.

Sorafenib and chemoembolization of the liver (TACE) have both produced increased survival in hepatocellular carcinoma (HCC). Some patients cannot tolerate TACE due to portal vein thrombosis or risk of liver failure. In this pilot trial, we aimed to combine intrahepatic infusion (IA) of cisplatin or carboplatin with sorafenib for unresectable HCC.Patients with Child's A or early B received IA cisplatin or carboplatin every 6 weeks with oral sorafenib. MRI/CT scans were performed every 6 weeks.Eleven patients were accrued. Of 10 evaluable patients, 6 had clinical benefit (4 partial responses for 2+, 3+, 8+ and 18 months, 2 minor responses). Two patients were down-staged enough for ablation therapy or liver transplant and remain free of disease for 32+ and 36+ months. Toxicity was generally tolerable.Preliminary results are encouraging and this combination may down-stage some patients with unresectable disease.

PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients. PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m2 bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m2 bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat–overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate. RESULTS: Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P = .004) and showed a trend for improved survival in the ITT population (P = .125). Grade 3 and 4 adverse events were comparable in the two arms. CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.

Purpose The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX). Patients and Methods Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) ≥ 60%, Cancer of the Liver Italian Program (CLIP) score ≤ 3, and adequate organ function. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rates, and safety. The treatment groups were well-balanced with regards to age, sex, ethnic origin, and underlying liver disease. Randomization was stratified according to KPS and CLIP score. Results At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm. Conclusion NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.

Collagen type I production has been shown to play a role in malignant transformation. We examined procollagen type I expression in brain tumors and with histopathological grading. Expression levels of procollagen alpha 1 type 1 were determined in 5 glioma cell lines by RT-PCR, Northern, and Western blot analysis. In addition, 41 primary brain tumors and 2 metastatic lung cancers to the brain were examined by PCR. Of the 5 glioma cell line analyzed, 3 (glioma 1, SW-1783 and U-118) expressed procollagen alpha 1 type I and were sensitive to vitamin D3 (VD3). In contrast, 2 of the cell lines (U-373 and T-98G) lacked procollagen alpha 1 type 1 expression. In patients' samples, 14 of 15 anaplastic and low grade gliomas expressed procollagen alpha 1 type I, and 12 of the 14 expressed high levels. In contrast, only 12 of 21 high grade gliomas from patients expressed procollagen alpha 1 type1 and among these, only 4 of the 12 expressed high levels. Thus, there is an inversed correlation between procollagen alpha 1 type 1 expression and histopathological grading (R2=- 0.56, p=0.0005). Our data suggest that procollagen alpha 1 type I expression occurs more commonly in intermediate and low grade gliomas and may assist in histopathological grading.