Publications by authors named "John M Kirkwood"

338 Publications

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma.

J Clin Oncol 2021 May 12:JCO2100612. Epub 2021 May 12.

James Graham Brown Cancer Center, University of Louisville, Louisville, KY.

Purpose: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.

Methods: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.

Results: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.

Conclusion: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.
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http://dx.doi.org/10.1200/JCO.21.00612DOI Listing
May 2021

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis.

J Immunother Cancer 2021 May;9(5)

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.

Background: The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood.

Patients And Methods: E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034).

Results: Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found.

Conclusions: Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.
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http://dx.doi.org/10.1136/jitc-2021-002535DOI Listing
May 2021

GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells.

Front Oncol 2021 8;11:656453. Epub 2021 Apr 8.

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, United States.

We defined the lethal interaction between the novel therapeutic GZ17-6.02 and the standard of care combination of the MEK1/2 inhibitor trametinib and the B-RAF inhibitor dabrafenib in PDX isolates of cutaneous melanoma expressing a mutant B-RAF V600E protein. GZ17-6.02 interacted with trametinib/dabrafenib in an additive fashion to kill melanoma cells. Regardless of prior vemurafenib resistance, the drugs when combined interacted to prolong ATM S1981/AMPK T172 and eIF2α S51 phosphorylation and prolong the reduced phosphorylation of JAK2 Y1007, STAT3 Y705 and STAT5 Y694. In vemurafenib-resistant cells GZ17-6.02 caused a prolonged reduction in mTORC1 S2448, mTORC2 S2481 and ULK1 S757 phosphorylation; regardless of vemurafenib resistance, GZ17-6.02 caused a prolonged elevation in CD95 and FAS-L expression. Knock down of eIF2α, Beclin1, ATG5, ATM, AMPKα, CD95 or FADD significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with the kinase inhibitors. Expression of activated mTOR, activated STAT3, activated MEK1 or activated AKT significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with kinase inhibitors; protective effects that were significantly less pronounced in cells treated with trametinib/dabrafenib. Regardless of vemurafenib resistance, the drugs alone or in combination all reduced the expression of PD-L1 and increased the levels of MHCA, which was linked to degradation of multiple HDAC proteins. Our findings support the use of GZ17-6.02 in combination with trametinib/dabrafenib in the treatment of melanomas expressing mutant B-RAF V600E proteins.
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http://dx.doi.org/10.3389/fonc.2021.656453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061416PMC
April 2021

Melanoma-specific expression of the tumor suppressor proteins p16 and PTEN is a favorable prognostic factor in established melanoma brain metastases.

Melanoma Res 2021 06;31(3):264-267

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

PTEN and p16 frequently undergo (epi)genetic aberrations in melanoma resulting in decreased, or absent, protein levels. We investigated the prognostic significance of these tumor suppressor genes in melanoma brain metastases (MBMs). Immunohistochemical analysis was performed on archived tissue sections from craniotomies. Expression of PTEN and p16 was semiquantitatively scored (0-3 scale) in melanoma cells, glia, TILs, and endothelial cells of tumor-associated vessels and was compared among the different brain tumor cell compartments. Overall survival (OS) analysis was performed according to PTEN and p16 protein expression in melanoma cells. 58 patients (median age 56, 37 male) underwent craniotomy for MBMs before February 2014. The OS of patients with decreased, or absent, protein expression (0, 1+) of PTEN and p16 in melanoma cells was significantly shorter compared to that of patients with high (2+, 3+) expression (median OS 2.40 vs. 10.75 months and 4.1 vs. 8.1 months, respectively; Gehan-Breslow-Wilcoxon test P = 0.026 and P = 0.037, respectively). PTEN and p16 protein expression were significantly lower in TILs compared to melanoma cells (Mann-Whitney test P = 0.023 and P < 0.0001, respectively). Low/absent protein expression of PTEN/p16 is an adverse prognostic factor in MBMs. Surprisingly, expression of both PTEN and p16 proteins was significantly lower in TILs compared to melanoma cells. Proliferating (p16 absent/low) TILs within the brain with or without an active PI3K-Akt pathway (PTEN absent/low) may represent a favorable host response in MBMs. Thus, treatment of patients with MBMs with CDK4/6 or PI3K pathway inhibitors may result in an unfavorable, bystander, off-target effect on host immune response.
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http://dx.doi.org/10.1097/CMR.0000000000000731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086752PMC
June 2021

A phase 1 study of NY-ESO-1 vaccine + anti-CTLA4 antibody Ipilimumab (IPI) in patients with unresectable or metastatic melanoma.

Oncoimmunology 2021 Mar 26;10(1):1898105. Epub 2021 Mar 26.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1 tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD ( = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67) CD8 T cells and decreases in RORγt CD4 T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8 T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. : Ab = antibody; CTCAE = NCI Common Terminology Criteria for Adverse Events; DHFR/DHRP = dihydrofolate reductase; DLT = Dose-limiting toxicity; ELISA = enzyme-linked immunosorbent assay; IFA = incomplete Freund's adjuvant (Montanide ISA-51); IFNγ = Interferon gamma; IPI = Ipilimumab; irRC = immune-related response criteria; mIFH = multispectral immunofluorescence histology; OLP = NY-ESO-1 overlapping long peptides; PBMC = peripheral blood mononuclear cells; PD = Progressive disease; pICLC = poly-ICLC (Hiltonol), a TLR3/MDA-5 agonist; RLT = Regimen-limiting Toxicity; ROI = regions of interest; RT = room temperature; SAE = serious adverse event; SD = stable disease; TEAE = treatment-emergent adverse events; TLR = toll-like receptor; TME = tumor microenvironment; TRAE = treatment-related adverse events.
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http://dx.doi.org/10.1080/2162402X.2021.1898105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007150PMC
March 2021

State of Melanoma: An Historic Overview of a Field in Transition.

Hematol Oncol Clin North Am 2021 Feb 26;35(1):1-27. Epub 2020 Oct 26.

University of Pittsburgh, Melanoma Center, UPMC Hillman, Suite L1.32c Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15232, USA. Electronic address:

The management of melanoma significantly improved within the last 25 years. Chemotherapy was the first approved systemic therapeutic approach and resulted in a median overall of survival less than 1 year, without survival improvement in phase III trials. High-dose interferon α2b and IL-2 were introduced for resectable high-risk and advanced disease, respectively, resulting in improved survival and response rates. The anti-CTLA4 and anti-programmed death 1 monoclonal antibodies along with BRAF/MEK targeted therapies are the dominant therapeutic classes of agent for melanoma. This article provides an historic overview of the evolution of melanoma management.
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http://dx.doi.org/10.1016/j.hoc.2020.09.003DOI Listing
February 2021

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

Clin Cancer Res 2021 Mar 22. Epub 2021 Mar 22.

H. Lee Moffit Cancer Center and Research Institute, Tampa, Florida.

Purpose: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.

Patients And Methods: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m/day i.v., 5 days per week for 4 weeks, then 10 MU/m/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.

Results: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR ( = 0.002 and = 0.008, respectively).

Conclusions: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4301DOI Listing
March 2021

Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma.

Front Oncol 2021 1;11:640314. Epub 2021 Mar 1.

Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

The advent of first and second-generation immune checkpoint blockade (ICI) has resulted in improved survival of patients with metastatic melanoma over the past decade. However, the majority of patients ultimately progress despite these treatments, which has served as an impetus to consider a range of subsequent therapies. Many of the next generation of immunotherapeutic agents focus on modifying the immune system to overcome resistance to checkpoint blockade. ICI resistance can be understood as primary, or acquired-where the latter is the most common scenario. While there are several postulated mechanisms by which resistance, particularly acquired resistance, occurs, the predominant escape mechanisms include T cell exhaustion, upregulation of alternative inhibitory checkpoint receptors, and alteration of the tumor microenvironment (TME) into a more suppressive, anti-inflammatory state. Therapeutic agents in development are designed to work by combating one or more of these resistance mechanisms. These strategies face the added challenge of minimizing immune-related toxicities, while improving antitumor efficacy. This review focuses upon the following categories of novel therapeutics: 1) alternative inhibitory receptor pathways; 2) damage- or pathogen-associated molecular patterns (DAMPs/PAMPs); and 3) immune cell signaling mediators. We present the current state of these therapies, including preclinical and clinical data available for these targets under development.
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http://dx.doi.org/10.3389/fonc.2021.640314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958874PMC
March 2021

Proteomic profile of melanoma cell-derived small extracellular vesicles in patients' plasma: a potential correlate of melanoma progression.

J Extracell Vesicles 2021 Feb 11;10(4):e12063. Epub 2021 Feb 11.

UPMC Hillman Cancer Center University of Pittsburgh Cancer Institute Pittsburgh Pennsylvania USA.

Molecular profiling of small extracellular vesicles (sEV) isolated from plasma of cancer patients emerges as promising strategy for biomarkers discovery. We investigated the proteomic profiles of sEV immunoselected using anti-CSPG4 antibodies from 15 melanoma patients' plasma. The proteomes of sEV separated into melanoma cell-derived (MTEX) and non-malignant cell-derived (NMTEX) were compared using high-resolution mass spectrometry. Paired analysis identified the MTEX-associated profile of 16 proteins that discriminated MTEX from NMETEX. We also identified the MTEX profile that discriminated between seven patients with no evidence of melanoma (NED) after therapy and eight with progressive disease (PD). Among 75 MTEX proteins overexpressed in PD patients, PDCD6IP (ALIX) had the highest discriminating value, while CNTN1 (contactin-1) was upregulated only in MTEX of NED patients. This is the first report documenting that proteomes of tumour-derived sEV in patients' plasma discriminate cancer from non-cancer and identify proteins with potential to serve as prognostic biomarkers in melanoma.
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http://dx.doi.org/10.1002/jev2.12063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876545PMC
February 2021

Early Cortisol and Inflammatory Responses to Parental Cancer and Their Impact on Functional Impairment in Youth.

J Clin Med 2021 Feb 4;10(4). Epub 2021 Feb 4.

Department of Psychiatry, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh, PA 15213, USA.

Purpose: Chronic stress is associated with increased risk for maladaptive psychological responses during childhood, adolescence, and young adulthood. Adults exposed to chronic stress during childhood exhibit dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity and inflammation. There are no studies examining the impact of stress on biological stress responses and functional impairment in adolescents and young adults early after the onset of a stressor.

Methods: The sample consisted of 59 offspring, aged 11-25 years, 33 of parents diagnosed with cancer and 26 controls from families with no cancer or severe chronic illness in parents or siblings. Cancer patients and their families were recruited within an average of 62 days (SD = 35.9) and followed at 6 and 9 months later. Functional impairment was assessed and hair cortisol concentrations (HCC), salivary cortisol, and inflammatory markers were measured. Mixed regression analyses were conducted.

Results: The stress group showed higher functional impairment (β = -5.5, 95% CI (-10.4, -0.06), = 0.03, d= -0.40) and HCC (β = 10.5, 95% CI (-5.5, -0.50), < 0.001, d = 1.43). However, HCC were reduced over time in the stress group (β= -0.3, 95% CI (-0.04, -0.01), < 0.001, d = -1.08). Higher total cortisol output was associated with increased functional impairment over time (β = -3.0, 95% CI (-5.5, -0.5), = 0.02, d = -0.60).

Conclusions: Parental cancer is associated with early increase in cortisol, which was associated with increased functional impairment in offspring. Clinicians need to assess and monitor psychiatric symptoms and functioning in these offspring early on following parental cancer diagnosis.
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http://dx.doi.org/10.3390/jcm10040576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913784PMC
February 2021

Brain Tumor Microenvironment and Angiogenesis in Melanoma Brain Metastases.

Front Oncol 2020 21;10:604213. Epub 2021 Jan 21.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Background: High tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.

Methods: Brain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.

Results: The patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.

Conclusions: ICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.
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http://dx.doi.org/10.3389/fonc.2020.604213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860978PMC
January 2021

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.

Science 2021 02;371(6529):595-602

Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8 T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
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http://dx.doi.org/10.1126/science.abf3363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097968PMC
February 2021

CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma.

PLoS One 2021 11;16(1):e0245287. Epub 2021 Jan 11.

Department of Cutaneous Oncology and Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

Patients with locally/regionally advanced melanoma were treated with neoadjuvant combination immunotherapy with high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens were obtained prior to the initiation of neoadjuvant therapy, at the time of surgery and progression if available. In this study, gene expression profiles of tumor specimens (N = 27) were investigated using the NanoString nCounter® platform to evaluate associations with clinical outcomes (pathologic response, radiologic response, relapse-free survival (RFS), and overall survival (OS)) and define biomarkers associated with tumor response. The Tumor Inflammation Signature (TIS), an 18-gene signature that enriches for response to Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated for association with clinical response and survival. It was observed that neoadjuvant ipilimumab-HDI therapy demonstrated an upregulation of immune-related genes, chemokines, and transcription regulator genes involved in immune cell activation, function, or cell proliferation. Importantly, increased expression of baseline pro-inflammatory genes CCL19, CD3D, CD8A, CD22, LY9, IL12RB1, C1S, C7, AMICA1, TIAM1, TIGIT, THY1 was associated with longer OS (p < 0.05). In addition, multiple genes that encode a component or a regulator of the extracellular matrix such as MMP2 and COL1A2 were identified post-treatment as being associated with longer RFS and OS. In all baseline tissues, high TIS scores were associated with longer OS (p = 0.0166). Also, downregulated expression of cell proliferation-related genes such as CUL1, CCND1 and AAMP at baseline was associated with pathological and radiological response (unadjusted p < 0.01). In conclusion, we identified numerous genes that play roles in multiple biological pathways involved in immune activation, immune suppression and cell proliferation correlating with pathological/radiological responses following neoadjuvant immunotherapy highlighting the complexity of immune responses modulated by immunotherapy. Our observations suggest that TIS may be a useful biomarker for predicting survival outcomes with combination immunotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245287PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799833PMC
May 2021

The State of Melanoma: Emergent Challenges and Opportunities.

Clin Cancer Res 2021 May 7;27(10):2678-2697. Epub 2021 Jan 7.

University of Pittsburgh, Pittsburgh, Pennsylvania.

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4092DOI Listing
May 2021

Society for Immunotherapy of Cancer clinical and biomarkers data sharing resource document: Volume II-practical challenges.

J Immunother Cancer 2020 12;8(2)

John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, Nottinghamshire, UK

The development of strongly predictive validated biomarkers is essential for the field of immuno-oncology (IO) to advance. The highly complex, multifactorial data sets required to develop these biomarkers necessitate effective, responsible data-sharing efforts in order to maximize the scientific knowledge and utility gained from their collection. While the sharing of clinical- and safety-related trial data has already been streamlined to a large extent, the sharing of biomarker-aimed clinical trial derived data and data sets has been met with a number of hurdles that have impaired the progression of biomarkers from hypothesis to clinical use. These hurdles include technical challenges associated with the infrastructure, technology, workforce, and sustainability required for clinical biomarker data sharing. To provide guidance and assist in the navigation of these challenges, the Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to outline the challenges that researchers currently face, both at the conceptual level (Volume I) and at the technical level (Volume II). The committee also suggests possible solutions to these problems in the form of professional standards and harmonized requirements for data sharing, assisting in continued progress toward effective, clinically relevant biomarkers in the IO setting.
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http://dx.doi.org/10.1136/jitc-2020-001472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745522PMC
December 2020

Unbiased High-Throughput Drug Combination Pilot Screening Identifies Synergistic Drug Combinations Effective against Patient-Derived and Drug-Resistant Melanoma Cell Lines.

SLAS Discov 2020 Nov 18:2472555220970917. Epub 2020 Nov 18.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.

We describe the development, optimization, and validation of 384-well growth inhibition assays for six patient-derived melanoma cell lines (PDMCLs), three wild type (WT) for and three with V600E- mutations. We conducted a pilot drug combination (DC) high-throughput screening (HTS) of 45 pairwise 4×4 DC matrices prepared from 10 drugs in the PDMCL assays: two B-Raf inhibitors (BRAFi), a MEK inhibitor (MEKi), and a methylation agent approved for melanoma; cytotoxic topoisomerase II and DNA methyltransferase chemotherapies; and drugs targeting the base excision DNA repair enzyme APE1 (apurinic/apyrimidinic endonuclease-1/redox effector factor-1), SRC family tyrosine kinases, the heat shock protein 90 (HSP90) molecular chaperone, and histone deacetylases.Pairwise DCs between dasatinib and three drugs approved for melanoma therapy-dabrafenib, vemurafenib, or trametinib-were flagged as synergistic in PDMCLs. Exposure to fixed DC ratios of the SRC inhibitor dasatinib with the BRAFis or MEKis interacted synergistically to increase PDMCL sensitivity to growth inhibition and enhance cytotoxicity independently of PDMCL status. These DCs synergistically inhibited the growth of mouse melanoma cell lines that either were dabrafenib-sensitive or had acquired resistance to dabrafenib with cross resistance to vemurafenib, trametinib, and dasatinib. Dasatinib DCs with dabrafenib, vemurafenib, or trametinib activated apoptosis and increased cell death in melanoma cells independently of their status or their drug resistance phenotypes. These preclinical in vitro studies provide a data-driven rationale for the further investigation of DCs between dasatinib and BRAFis or MEKis as candidates for melanoma combination therapies with the potential to improve outcomes and/or prevent or delay the emergence of disease resistance.
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http://dx.doi.org/10.1177/2472555220970917DOI Listing
November 2020

Indoor tanning exposure in association with multiple primary melanoma.

Cancer 2021 Feb 10;127(4):560-568. Epub 2020 Nov 10.

Department of Medicine, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background: Patients with primary cutaneous melanoma are at increased risk for subsequent new primary melanomas. Indoor tanning is a recognized risk factor for melanoma. This study was aimed at determining the association between indoor tanning and the occurrence of multiple primary melanoma.

Methods: This was a retrospective case-control study of cases with multiple primary melanoma and sex-matched controls with single primary melanoma retrieved at a 1:2 ratio from the Biological Sample and Nevus Bank of the Melanoma Center of the University of Pittsburgh Cancer Institute. Logistic regression models were used to examine the association between multiple primary melanoma and risk factors.

Results: In total, 330 patients (39.1% men) with a median age of 51 years were enrolled. Compared with patients who had a single primary melanoma, patients with multiple melanomas were younger at the diagnosis of their first primary melanoma and were more likely to be discovered at stage 0 or I and to have had indoor tanning exposure, a family history of melanoma, atypical moles, dysplastic nevi, and a Breslow thickness less than 1 mm. Compared with patients' first melanomas, subsequent melanomas were more likely to be thinner or in situ. The estimated probability of the locus for the second primary being the same as that for the first primary melanoma was 34%. In a multivariate analysis after adjustments for age, a family history of melanoma, the presence of atypical and dysplastic nevi, and recreational sun exposure, indoor tanning remained significantly associated with the occurrence of multiple primary melanoma (odds ratio, 2.75; 95% confidence interval, 1.07-7.08; P = .0356).

Conclusions: Indoor tanning is associated with an increased risk of second primary melanoma. Subsequent melanomas are more likely to be thin or in situ and to occur in different anatomic locations.
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http://dx.doi.org/10.1002/cncr.33307DOI Listing
February 2021

Society for Immunotherapy of Cancer clinical and biomarkers data sharing resource document: Volume I-conceptual challenges.

J Immunother Cancer 2020 10;8(2)

ESSA Pharma Inc, South San Francisco, California, USA

The sharing of clinical trial data and biomarker data sets among the scientific community, whether the data originates from pharmaceutical companies or academic institutions, is of critical importance to enable the development of new and improved cancer immunotherapy modalities. Through data sharing, a better understanding of current therapies in terms of their efficacy, safety and biomarker data profiles can be achieved. However, the sharing of these data sets involves a number of stakeholder groups including patients, researchers, private industry, scientific journals and professional societies. Each of these stakeholder groups has differing interests in the use and sharing of clinical trial and biomarker data, and the conflicts caused by these differing interests represent significant obstacles to effective, widespread sharing of data. Thus, the Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to identify the current barriers to biomarker data sharing in immuno-oncology (IO) and to help in establishing professional standards for the responsible sharing of clinical trial data. The conclusions of the committee are described in two position papers: Volume I-conceptual challenges and Volume II-practical challenges, the first of which is presented in this manuscript. Additionally, the committee suggests actions by key stakeholders in the field (including organizations and professional societies) as the best path forward, encouraging the cultural shift needed to ensure responsible data sharing in the IO research setting.
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http://dx.doi.org/10.1136/jitc-2020-001389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604864PMC
October 2020

Dysregulated NF-κB-Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma.

Cancer Immunol Res 2020 12 13;8(12):1554-1567. Epub 2020 Oct 13.

Parker Institute for Cancer Immunotherapy, and University of California San Francisco, Microbiology and Immunology, San Francisco, California.

Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic but are rarely effective in promoting objective clinical responses. To identify critical molecules for activation of effective antitumor immunity, we have profiled autologous dendritic cell (DC) vaccines used to treat 35 patients with melanoma. We showed that checkpoint molecules induced by maturation correlated with DC vaccine activity. Melanoma patient DCs had reduced expression of cell surface inducible T-cell costimulator ligand (ICOSL) and had defective intrinsic NF-κB signaling. Chromatin immunoprecipitation assays revealed NF-κB-dependent transcriptional regulation of ICOSL expression by DCs. Blockade of ICOSL on DCs reduced priming of antigen-specific CD8 and CD4 T cells from naïve donors Concentration of extracellular/soluble ICOSL released from vaccine DCs positively correlated with patient clinical outcomes, which we showed to be partially regulated by ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-κB signaling, the regulation of matrix metalloproteinases, and DC-derived ICOSL in the specific priming of cognate T-cell responses in the cancer setting. This study supports the implementation of targeted strategies to augment these pathways for improved immunotherapeutic outcomes in patients with cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018573PMC
December 2020

Molecular and immunological associations of elevated serum lactate dehydrogenase in metastatic melanoma patients: A fresh look at an old biomarker.

Cancer Med 2020 11 5;9(22):8650-8661. Epub 2020 Oct 5.

Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Elevated serum lactate dehydrogenase (sLDH) is associated with poor clinical outcomes in patients with stage IV metastatic melanoma (MM). It is currently unknown if sLDH elevation correlates with distinct molecular, metabolic, or immune features of melanoma metastases. The identification of such features may identify rational therapeutic strategies for patients with elevated sLDH. Thus, we obtained sLDH levels for melanoma patients with metastases who had undergone molecular and/or immune profiling. Our analysis of multi-omics data from independent cohorts of melanoma metastases showed that elevated sLDH was not significantly associated with differences in immune cell infiltrate, point mutations, DNA copy number variations, promoter methylation, RNA expression, or protein expression in melanoma metastases. The only significant association observed for elevated sLDH was with the number of metastatic sites of disease. Our data support that sLDH correlates with disease burden, but not specific molecular or immunological phenotypes, in metastatic melanoma.
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http://dx.doi.org/10.1002/cam4.3474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666738PMC
November 2020

Cancer vaccine induces potent T cell responses - but is it enough?

Nat Rev Clin Oncol 2020 12;17(12):721-722

University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1038/s41571-020-00437-1DOI Listing
December 2020

Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.

N Engl J Med 2020 09 2;383(12):1139-1148. Epub 2020 Sep 2.

From University Hospital Zurich Skin Cancer Center, Zurich, Switzerland (R.D.); University Hospital Schleswig-Holstein, Kiel (A. Hauschild), University Hospital Essen, Essen (D.S.), and German Cancer Consortium, Heidelberg (D.S.) - all in Germany; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.S.), Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M.M.), and the Melanoma Oncology Unit, Veneto Oncology Institute-IRCCS, Padua (V.C.S.) - all in Italy; Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Brisbane (V.A.), Alfred Hospital, Melbourne, VIC (A. Haydon), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia; the Melanoma Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh (J.M.K.); Royal Marsden NHS Foundation Trust, London (J.L.), and the Northern Centre for Cancer Care, Freeman Hospital and Newcastle University, Newcastle upon Tyne (R.P.) - both in the United Kingdom; Oslo University Hospital, the Norwegian Radium Hospital, Oslo (M.N.); Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux (C.D.), Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif (C.R.), Université de Lille, INSERM Unité 1189, Lille (L.M.), and the Medical Oncology Department, Centre Eugène Marquis, Rennes (T.L.) - all in France; Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv - both in Israel (J.S.); Novartis Healthcare, Hyderabad, India (K.D.); and Novartis Pharmaceuticals, East Hanover, NJ (E.G., M.T.).

Background: In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed.

Methods: We randomly assigned 870 patients who had resected stage III melanoma with V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached.

Results: The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.

Conclusions: In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).
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http://dx.doi.org/10.1056/NEJMoa2005493DOI Listing
September 2020

Prognostic Gene Expression Profiling in Cutaneous Melanoma: Identifying the Knowledge Gaps and Assessing the Clinical Benefit.

JAMA Dermatol 2020 09;156(9):1004-1011

Department of Dermatology, Tufts Medical Center, Boston, Massachusetts.

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.

Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.

Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.

Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.

Conclusions And Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.
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http://dx.doi.org/10.1001/jamadermatol.2020.1729DOI Listing
September 2020

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.

Sci Immunol 2020 07;5(49)

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene-3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3 intrinsically perturbs CD4 T conventional cells (T), limiting their capacity to provide CD8 T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4 T in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.
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http://dx.doi.org/10.1126/sciimmunol.abc2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901539PMC
July 2020

IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma.

Clin Cancer Res 2020 10 26;26(20):5520-5533. Epub 2020 Jun 26.

Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.

Purpose: Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell-mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell-mediated tumor reactivity.

Experimental Design: We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell-mediated cytotoxicity and in two mouse models.

Results: NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT NK cells, TIGIT NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155 MHC class I-deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell-mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell-mediated melanoma cytotoxicity and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade.

Conclusions: Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell-mediated destruction of MHC class I-deficient melanoma, which are refractory to CD8 T-cell-mediated immunity..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045409PMC
October 2020

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.

J Immunother Cancer 2020 06;8(1)

Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.

Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.

Methods: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.

Results: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).

Conclusions: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.
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http://dx.doi.org/10.1136/jitc-2019-000331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319717PMC
June 2020

Clinical Development of BRAF plus MEK Inhibitor Combinations.

Trends Cancer 2020 09 13;6(9):797-810. Epub 2020 Jun 13.

Department of Medicine, Division of Medical Oncology University of Pittsburgh, and Melanoma Program, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA 15232, USA.

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.
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http://dx.doi.org/10.1016/j.trecan.2020.05.009DOI Listing
September 2020

Impact of checkpoint blockade on cancer vaccine-activated CD8+ T cell responses.

J Exp Med 2020 07;217(7)

University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.

Immune and molecular profiling of CD8 T cells of patients receiving DC vaccines expressing three full-length melanoma antigens (MAs) was performed. Antigen expression levels in DCs had no significant impact on T cell or clinical responses. Patients who received checkpoint blockade before DC vaccination had higher baseline MA-specific CD8 T cell responses but no evidence for improved functional responses to the vaccine. Patients who showed the best clinical responses had low PD-1 expression on MA-specific T cells before and after DC vaccination; however, blockade of PD-1 during antigen presentation by DC had minimal functional impact on PD-1high MA-specific T cells. Gene and protein expression analyses in lymphocytes and tumor samples identified critical immunoregulatory pathways, including CTLA-4 and PD-1. High immune checkpoint gene expression networks correlated with inferior clinical outcomes. Soluble serum PD-L2 showed suggestive positive association with improved outcome. These findings show that checkpoint molecular pathways are critical for vaccine outcomes and suggest specific sequencing of vaccine combinations.
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http://dx.doi.org/10.1084/jem.20191369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336310PMC
July 2020

Prognosis and Management of BRAF V600E-Mutated Pregnancy-Associated Melanoma.

Oncologist 2020 08 9;25(8):e1209-e1220. Epub 2020 Apr 9.

First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Laiko General Hospital, Athens, Greece.

Background: Approximately one third of women who develop melanoma at childbearing age are diagnosed during gestation or the postpartum period, facing pregnancy-associated melanoma (PAM). However, only some retrospective studies with heterogeneous data have analyzed the impact of pregnancy on melanoma development, and no evidence exists about the behavior and the management of BRAF-mutated disease.

Subjects, Materials, And Methods: In order to better describe the evolution of BRAF V600E-mutated PAM, we present here all consecutive cases diagnosed in our site during the last 7 years, recording oncological, obstetrical, and perinatal parameters, as well as the therapeutic decisions for both melanoma and gestation. Based on our institutional experience, we weigh the current published evidence and discuss upcoming clinical considerations about the prognosis of PAM, the role of BRAF status, and the possible treatment options during pregnancy in localized or advanced/metastatic disease. Five women were diagnosed with newly metastatic or relapsed BRAF V600E-mutated PAM (four during gestation and one in the 1st year postpartum) between 2012 and 2019. All of them developed extensive metastatic disease with multiple organ involvement, and four developed brain metastases. All cases experienced melanoma progression in less than 6 months under targeted therapy and died soon independently of the followed sequence of treatments. All the neonates were delivered alive and healthy, but one developed melanoma earlier than the second year of life.

Results: Reviewing the literature to confirm our unfavorable outcomes, no specific data on BRAF-mutated PAM were retrieved and current evidence still supports that the prognosis of PAM should be guided by the established risk factors, whereas the management of advanced/metastatic PAM should be evaluated on a case-by-case basis.

Conclusion: More data are required to ascertain whether BRAF-mutated profile adversely affects PAM outcome, although the clinicians should be aware to detect any potential melanoma lesion during pregnancy as soon as possible, treating it locally, regardless of its BRAF status.

Implications For Practice: The prognosis and management of pregnancy-associated melanoma whether BRAF-mutated or wild type, is currently guided by the same parameters as in the nonpregnant condition. In this special nontrial subpopulation, BRAF-mutated status seems to have a detrimental effect on disease outcome, independently of the following treatments. In early stage melanoma, wide local excision with or without sentinel lymph node dissection may be curative at any trimester of gestation, while in advanced/metastatic setting, therapeutic strategy including immune-checkpoint or BRAF/MEK inhibitors, is more challenging, regardless of BRAF status, and should be based on an individualized decision in each case at a multidisciplinary level.
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http://dx.doi.org/10.1634/theoncologist.2019-0747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418358PMC
August 2020

Systemic Therapy for Melanoma: ASCO Guideline.

J Clin Oncol 2020 11 31;38(33):3947-3970. Epub 2020 Mar 31.

Cleveland Clinic, Cleveland, OH.

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma.

Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature.

Results: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma.

Recommendations: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in -mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in -mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.
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http://dx.doi.org/10.1200/JCO.20.00198DOI Listing
November 2020