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Background : A single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive. Objective : To evaluate the rate of the G2019S* LRKK2 mutation among ethnically diverse, Jewish PD patients, MM patients, and Ashkenazi, Iraqi and Moroccan healthy controls. Patients and methods : Overall, 242 Jewish PD patients (155 Ashkenazim and 7 of mixed origin) and 169 Jewish MM patients (142 Ashkenazim) were genotyped for the G2019S mutation. In addition, 900 healthy ethnic Jewish controls (300 Ashkenazim, 300 Moroccans and 300 Iraqis) were similarly analyzed. Genotyping was performed using PCR amplification followed by restriction digest and gel electrophoresis. Statistical analysis was done using the Chi square test. Results : Overall 19/242 (7.9 %) of the PD patients (16/155 of Ashkenazim, 10.3 %; 3/87 of non-Ashkenazim, 3.4 %) harbored the G2019S LRKK2 mutation. The age at diagnosis of PD in mutation carriers was 60.6 plus or minus 10.9 years compared with an age at diagnosis of 61.1 plus or minus 13.4 years in non-carriers (p = 0.87). Nine of 38 familial Ashkenazi PD patients (23.68 %) carried the mutation, as did 2/169 MM patients (1.2 %; 2/142, 1.4 % of the Ashkenazim). A single mutation carrier of Ashkenazi origin was detected among 900 controls (0.3 % of the Ashkenazi controls). Conclusion : The G2019S*LRKK2 mutation is significantly more prevalent in Ashkenazi PD patients than in controls (p = 1 10-6), it is less commonly detected in non-Ashkenazi affected individuals, and its contribution to MM predisposition in Jewish individuals needs to be explored further.

Adoptive cell transfer (ACT) using autologous tumor infiltrating lymphocytes (TILs) was previously shown to yield clinical response in metastatic melanoma patients as an advanced line. Unfortunately, there is no reliable marker for predicting who will benefit from the treatment. We analyzed TIL samples from the infusion bags used for treatment of 57 metastatic melanoma patients and compared their microRNA profiles. The discovery cohort included six responding patients and seven patients with progressive disease, as defined by RECIST1.1. High throughput analysis with NanoString nCounter demonstrated significantly higher levels of miR-34a-5p and miR-22-3p among TIL from non-responders. These results were validated in TIL infusion bag samples from an independent cohort of 44 patients, using qRT-PCR of the individual microRNAs. Using classification trees, a data-driven predictive model for response was built, based on the level of expression of these microRNAs. Patients that achieved stable disease were classified with responders, setting apart the patients with progressive disease. Moreover, the expression levels of miR-34a-5p in the infused TIL created distinct survival groups, which strongly supports its role as a potential biomarker for TIL-ACT therapy. Indeed, when tested against autologous melanoma cells, miRLow TIL cultures exhibited significantly higher cytotoxic activity than miRHigh TIL cultures, and expressed features of terminally exhausted effectors. Finally, overexpression of miR-34a-5p or miR-22-3p in TIL inhibited their cytotoxic ability in vitro. Overall, we show that a two-microRNA signature correlates with failure of TIL-ACT therapy and survival in melanoma patients.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their efficacy remains limited. Therefore, there is a clear need for new anti-tumor agents. HVEM (Herpes Virus Entry Mediator) plays a regulatory role in immunity, making it a promising cancer therapeutic target. EXPERIMENTAL DESIGN: We have developed Anti-4CB1, a fully human HVEM-BTLA and HVEM-CD160 blocking mAb and tested its anti-tumor activity in various in-vitro, ex-vivo and in-vivo models, alone or in combination with Anti-PD1. Finally, we analyzed HVEM expression in serum samples and melanoma tumor tissues and its correlation with HVEM and PD1 blockade treatment response. RESULTS: In-vitro assays demonstrated enhanced melanoma cell killing by autologous TILs in the presence of Anti-4CB1. In addition, Anti-4CB1 significantly increased cytotoxicity by up to 233% in a variety of ex-vivo cancer tissue samples of different indications. Notably, Anti-4CB1 demonstrated effectiveness in samples where Anti-PD1 was ineffective. In addition, significant anti-tumor activity at 10 mg/kg in combination with Anti-PD1 (TGI 95% p=0.0001) or at 25 mg/kg as monotherapy (TGI 50% p=0.0096) was demonstrated in a colon carcinoma transgenic mice model. Moreover, significant anti-tumor activity was observed in a mouse ImmunoGraft model (TGI 53% p=0.0102 as monotherapy). Finally, we demonstrated that HVEM expression correlated with response to Anti-HVEM and Anti-PD1 treatments. DISCUSSION: We describe the development of Anti-4CB1, a fully human anti-HVEM mAb, blocking HVEM-BTLA and HVEM-CD160 human interactions and enhancing lymphocytes cytotoxicity against various cancer cells ex-vivo. In-vivo, Anti-4CB1 showed promising anti-tumor effects, particularly in combination with Anti-PD1, suggesting its therapeutic potential. Finally, HVEM expression may serve as a predictive marker for Anti-HVEM and Anti-PD1 treatments response, offering potential diagnostic utility in patient selection for these immunotherapies. These results support Anti-4CB1 potential as an anti-cancer therapeutic agent.Competing Interest StatementThe authors have declared no competing interest.

Adoptive cell transfer therapy with reactive T cells is one of the most promising immunotherapeutic modalities for metastatic melanoma patients. Homing of the transferred T cells to all tumor sites in sufficient numbers is of great importance. Here, we seek to exploit endogenous chemotactic signals in order to manipulate and enhance the directional trafficking of transferred T cells toward melanoma. Chemokine profiling of 15 melanoma cultures shows that CXCL1 and CXCL8 are abundantly expressed and secreted from melanoma cultures. However, the complimentary analysis on 40 melanoma patient-derived tumor-infiltrating lymphocytes (TIL) proves that the corresponding chemokine receptors are either not expressed (CXCR2) or expressed at low levels (CXCR1). Using the in vitro transwell system, we demonstrate that TIL cells preferentially migrate toward melanoma and that endogenously expressing CXCR1 TIL cells are significantly enriched among the migrating lymphocytes. The role of the chemokines CXCL1 and CXCL8 is demonstrated by partial abrogation of this enrichment with anti-CXCL1 and anti-CXCL8 neutralizing antibodies. The role of the chemokine receptor CXCR1 is validated by the enhanced migration of CXCR1-engineered TIL cells toward melanoma or recombinant CXCL8. Cytotoxicity and IFNγ secretion activity are unaltered by CXCR1 expression profile. Taken together, these results mark CXCR1 as a candidate for genetic manipulations to enhance trafficking of adoptively transferred T cells. This approach is complimentary and potentially synergistic with other genetic strategies designed to enhance anti-tumor potency.

Background A single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive. Objective To evaluate the rate of the G2019S * LRKK2 mutation among ethnically diverse, Jewish PD patients, MM patients, and Ashkenazi, Iraqi and Moroccan healthy controls. Patients and methods Overall, 242 Jewish PD patients (155 Ashkenazim and 7 of mixed origin) and 169 Jewish MM patients (142 Ashkenazim) were genotyped for the G2019S mutation. In addition, 900 healthy ethnic Jewish controls (300 Ashkenazim, 300 Moroccans and 300 Iraqis) were similarly analyzed. Genotyping was performed using PCR amplification followed by restriction digest and gel electrophoresis. Statistical analysis was done using the Chi square test. Results Overall 19/242 (7.9 %) of the PD patients (16/155 of Ashkenazim, 10.3 %; 3/87 of non-Ashkenazim, 3.4 %) harbored the G2019S LRKK2 mutation. The age at diagnosis of PD in mutation carriers was 60.6 ± 10.9 years compared with an age at diagnosis of 61.1 ± 13.4 years in non-carriers (p = 0.87). Nine of 38 familial Ashkenazi PD patients (23.68 %) carried the mutation, as did 2/169 MM patients (1.2 %; 2/142, 1.4 % of the Ashkenazim). A single mutation carrier of Ashkenazi origin was detected among 900 controls (0.3 % of the Ashkenazi controls). Conclusion The G2019S*LRKK2 mutation is significantly more prevalent in Ashkenazi PD patients than in controls (p = 1 × 10 –6 ), it is less commonly detected in non-Ashkenazi affected individuals, and its contribution to MM predisposition in Jewish individuals needs to be explored further.