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Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes

Ibrahim, Milad; Illa-Bochaca, Irineu; Fa"™ak, Faisal; Monson, Kelsey R.; Ferguson, Robert; Lyu, Chen; Vega-Saenz de Miera, Eleazar; Johannet, Paul; Chou, Margaret; Mastroianni, Justin; Darvishian, Farbod; Kirchhoff, Tomas; Zhong, Judy; Krogsgaard, Michelle; Osman, Iman
Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials.
SCOPUS:85182244291
ISSN: 2072-6694
CID: 5629852

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st-3rd, 2022-Naples, Italy)

Ascierto, Paolo A; Agarwala, Sanjiv S; Warner, Allison Betof; Ernstoff, Marc S; Fox, Bernard A; Gajewski, Thomas F; Galon, Jérôme; Garbe, Claus; Gastman, Brian R; Gershenwald, Jeffrey E; Kalinski, Pawel; Krogsgaard, Michelle; Leidner, Rom S; Lo, Roger S; Menzies, Alexander M; Michielin, Olivier; Poulikakos, Poulikos I; Weber, Jeffrey S; Caracò, Corrado; Osman, Iman; Puzanov, Igor; Thurin, Magdalena
Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1st-3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies.
PMCID:10375730
PMID: 37507765
ISSN: 1479-5876
CID: 5594222

Author Correction: Molecular mechanism of phosphopeptide neoantigen immunogenicity

Patskovsky, Yury; Natarajan, Aswin; Patskovska, Larysa; Nyovanie, Samantha; Joshi, Bishnu; Morin, Benjamin; Brittsan, Christine; Huber, Olivia; Gordon, Samuel; Michelet, Xavier; Schmitzberger, Florian; Stein, Robert B; Findeis, Mark A; Hurwitz, Andy; Van Dijk, Marc; Chantzoura, Eleni; Yague, Alvaro S; Pollack Smith, Daniel; Buell, Jennifer S; Underwood, Dennis; Krogsgaard, Michelle
PMID: 37500629
ISSN: 2041-1723
CID: 5618892

Molecular mechanism of phosphopeptide neoantigen immunogenicity

Patskovsky, Yury; Natarajan, Aswin; Patskovska, Larysa; Nyovanie, Samantha; Joshi, Bishnu; Morin, Benjamin; Brittsan, Christine; Huber, Olivia; Gordon, Samuel; Michelet, Xavier; Schmitzberger, Florian; Stein, Robert B; Findeis, Mark A; Hurwitz, Andy; Van Dijk, Marc; Buell, Jennifer S; Underwood, Dennis; Krogsgaard, Michelle
Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL747-755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization.
PMCID:10290117
PMID: 37353482
ISSN: 2041-1723
CID: 5538512

Catch bond models may explain how force amplifies TCR signaling and antigen discrimination

Choi, Hyun-Kyu; Cong, Peiwen; Ge, Chenghao; Natarajan, Aswin; Liu, Baoyu; Zhang, Yong; Li, Kaitao; Rushdi, Muaz Nik; Chen, Wei; Lou, Jizhong; Krogsgaard, Michelle; Zhu, Cheng
The TCR integrates forces in its triggering process upon interaction with pMHC. Force elicits TCR catch-slip bonds with strong pMHCs but slip-only bonds with weak pMHCs. We develop two models and apply them to analyze 55 datasets, demonstrating the models' ability to quantitatively integrate and classify a broad range of bond behaviors and biological activities. Comparing to a generic two-state model, our models can distinguish class I from class II MHCs and correlate their structural parameters with the TCR/pMHC's potency to trigger T cell activation. The models are tested by mutagenesis using an MHC and a TCR mutated to alter conformation changes. The extensive comparisons between theory and experiment provide model validation and testable hypothesis regarding specific conformational changes that control bond profiles, thereby suggesting structural mechanisms for the inner workings of the TCR mechanosensing machinery and plausible explanations of why and how force may amplify TCR signaling and antigen discrimination.
PMCID:10163261
PMID: 37147290
ISSN: 2041-1723
CID: 5503182

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A.; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S.; Rahma, Osama E.; Suarez-Almazor, Maria E.; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35"“3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95"“5.66), P =.054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P =.53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
SCOPUS:85175548637
ISSN: 2162-4011
CID: 5616442

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S; Rahma, Osama E; Suarez-Almazor, Maria E; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
PMCID:10732692
PMID: 38126033
ISSN: 2162-402x
CID: 5626492

Hybrid and vaccine-induced immunity against SAR-CoV-2 in MS patients on different disease-modifying therapies

Kister, Ilya; Curtin, Ryan; Pei, Jinglan; Perdomo, Katherine; Bacon, Tamar E; Voloshyna, Iryna; Kim, Joseph; Tardio, Ethan; Velmurugu, Yogambigai; Nyovanie, Samantha; Valeria Calderon, Andrea; Dibba, Fatoumatta; Stanzin, Igda; Samanovic, Marie I; Raut, Pranil; Raposo, Catarina; Priest, Jessica; Cabatingan, Mark; Winger, Ryan C; Mulligan, Mark J; Patskovsky, Yury; Silverman, Gregg J; Krogsgaard, Michelle
OBJECTIVE:To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patients on different disease-modifying therapies (DMTs) and to assess the impact of vaccine product and race/ethnicity on post-vaccination immune responses. METHODS:Consecutive MS patients from NYU MS Care Center (New York, NY), aged 18-60, who completed primary COVID-19 vaccination series ≥6 weeks previously were evaluated for SARS CoV-2-specific antibody responses with electro-chemiluminescence and multiepitope bead-based immunoassays and, in a subset, live virus immunofluorescence-based microneutralization assay. SARS CoV-2-specific cellular responses were assessed with cellular stimulation TruCulture IFNγ and IL-2 assay and, in a subset, with IFNγ and IL-2 ELISpot assays. Multivariate analyses examined associations between immunologic responses and prior COVID-19 infection while controlling for age, sex, DMT at vaccination, time-to-vaccine, and vaccine product. RESULTS:Between 6/01/2021 and 11/11/2021, 370 MS patients were recruited (mean age 40.6 years; 76% female; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly increased antibody and cellular post-vaccination responses compared to those without prior infection. Vaccine product and DMT class were independent predictors of antibody and cellular responses, while race/ethnicity was not. INTERPRETATION/CONCLUSIONS:Prior COVID-19 infection is associated with enhanced antibody and cellular post-vaccine responses independent of DMT class and vaccine type. There were no differences in immune responses across race/ethnic groups.
PMID: 36165097
ISSN: 2328-9503
CID: 5334142

Baseline Serum Autoantibody Signatures Predict Recurrence and Toxicity in Melanoma Patients Receiving Adjuvant Immune Checkpoint Blockade

Johannet, Paul; Liu, Wenke; Fenyo, David; Wind-Rotolo, Megan; Krogsgaard, Michelle; Mehnert, Janice M; Weber, Jeffrey S; Zhong, Judy; Osman, Iman
PURPOSE:Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab. EXPERIMENTAL DESIGN:This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915. RESULTS:In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98-6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59-86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38-7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84-37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48-28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10-212.50). CONCLUSIONS:Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility. See related commentary by Hassel and Luke, p. 3914.
PMID: 36106402
ISSN: 1557-3265
CID: 5335062

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 2nd - 4th, 2021, Italy)

Ascierto, Paolo A; Agarwala, Sanjiv S; Blank, Christian; Caracò, Corrado; Carvajal, Richard D; Ernstoff, Marc S; Ferrone, Soldano; Fox, Bernard A; Gajewski, Thomas F; Garbe, Claus; Grob, Jean-Jacques; Hamid, Omid; Krogsgaard, Michelle; Lo, Roger S; Lund, Amanda W; Madonna, Gabriele; Michielin, Olivier; Neyns, Bart; Osman, Iman; Peters, Solange; Poulikakos, Poulikos I; Quezada, Sergio A; Reinfeld, Bradley; Zitvogel, Laurence; Puzanov, Igor; Thurin, Magdalena
Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients.
PMCID:9440864
PMID: 36058945
ISSN: 1479-5876
CID: 5323262