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Background:Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands.Patients and Methods:We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti–PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis.Results:Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells.Conclusions:In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland–directed therapies or surgical resection.

Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling drives exhausted phenotypes on CD8 T cells. Importantly, we identify a novel function of Lpar5 to regulate CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a novel T cell directed therapy to improve dysfunctional anti-tumor immunity.

There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers.

Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials.

Subungual melanomas (SUM) arise beneath the nails of the hands and feet, and account for 0.7-3.5% of all malignant melanomas. Most studies include SUM in the category of acral melanoma, but understanding the specific features of SUM is critical for improving patient care. In this study, we performed a site-specific comparison of the clinical and molecular features between 54 cases of SUM and 78 cases of nonsubungual acral melanoma. Compared to patients with acral melanoma, patients with SUM were younger at diagnosis, had a higher prevalence of primary melanomas on the hand, and had more frequent reports of previous trauma at the tumor site. SUM was deeper than acral melanoma at diagnosis, which correlated with an increased frequency of metastases. Analysis of common melanoma driver genes revealed KIT and KRAS mutations were predominantly found in SUM, whereas BRAF and NRAS mutations occurred almost exclusively in acral melanoma. We also discovered molecular differences in the cell cycle pathway, where CDK4/CCND1 amplifications were more frequent in SUM and CDKN2A/B loss occurred mostly in acral melanoma, and in the PI3K/mTOR pathway, where RICTOR amplification and TSC1 K587R mutations were exclusively in SUM and PTEN loss and AKT1 mutations were exclusively in acral melanoma. Comparison of hand versus foot tumors revealed more frequent ulceration of SUM foot tumors, which correlated with more distal metastases and poorer overall survival. In summary, we find SUM are both clinically and molecularly distinct from acral melanoma, and our data suggest KIT, CDK4/6, and mTOR inhibitors may be particularly relevant and effective treatments for patients with SUM.

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options., Acral melanoma occurs on the soles of the feet, palms of the hands and in nail beds. Here, the authors reports the genomic landscape of 87 acral melanomas and find that some tumors harbor a UV signature and that the tumors are diverse at the levels of mutational signatures, structural aberrations and copy number signatures.

While much of the research concerning factors associated with responses to immunotherapies focuses on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosalassociated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting vitamin metabolites derived from bacteria. In this prospective clinical study, we sought to characterize MAIT cells in melanoma patients and determine their association with clinical outcomes. We identified tumor-infiltrating MAIT cells in melanomas across metastatic sites and found that the number of circulating MAIT cells is reduced in melanoma patients. However, circulating MAIT cell frequency is restored by anti-PD1 treatment in responding patients, correlating with treatment responses in which patients with high frequencies of MAIT cells exhibited improved overall survival. These data provide evidence for leveraging MAIT cells and their functions as novel targets for future therapies.

There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations. Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations, suggesting that BH3 mimetics, such as ABT-199 (venetoclax, a small molecule against BCL2), may be a potential therapeutic option for these patients. We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo. Our data indicate this combination induced cell death in a broad range of melanoma cell lines, including melanoma initiating cell populations, and was more potent in melanoma cells without BRAF-V600E/K mutations. Our knockdown/knockout experiments suggest that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, play a role in the combination-induced effects. Overall, our study supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma.

Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p p p > 0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.

Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.

9536 Background: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) reduces MDSC frequency. This analysis seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in advanced melanoma patients. Methods: This single arm, single institution, phase I/II study (NCT03200847) enrolled 24 patients diagnosed with stage IV melanoma. Eligible patients were over the age of 18 and had not been previously treated anti-PD-1 therapy. Treatment consisted of 200mg Q3W pembrolizumab plus the supplemental treatment of 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions of pembrolizumab, with patients continuing pembrolizumab for up to two years until confirmed disease progression or unacceptable toxicity. The primary endpoints were safety and reduction in circulating MDSCs. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) according to RECIST v1.1. Results: At data cut off (Feb, 2021) 22 patients were evaluable for tumor response. Median follow-up was 1.0 years (0.3-2 years). In general, the combination of pembrolizumab and ATRA was well tolerated. The most common treatment-related adverse events (AEs) were grade 1 or 2, including headache (22 pts, 92%), fatigue (18 pts, 75%), rash (16 pts, 66%), and nausea (8 pts, 33%), most of which corresponded with the 3-day course of ATRA treatment. Ten patients had grade 3 or higher AEs with most being common ICI-related AEs. The ORR was 60% and DCR was 83%. Six-month PFS rate was 62%. Excluding patients diagnosed with uveal melanoma (n = 2) the ORR was 72%, DCR was 86%, and the six-month PFS rate was 68%. Paired analysis showed sustained decreases in absolute numbers ( p = 0.002) and percentage ( p = 0.007) of circulating MDSCs (CD3-CD19-CD56-CD11b+CD33+HLA-DR-/low) 4-6 weeks after stopping ATRA. The study is ongoing and further data will be presented in the future. Conclusions: This study demonstrates that the combination of ATRA and pembrolizumab is well tolerated and suggests that reducing MDSCs with ATRA may enhance the efficacy of pembrolizumab. This strategy of targeting MDSCs in combination with pembrolizumab warrants further development. Research Funding: Merck. Clinical trial information: NCT03200847.

Cutaneous melanoma (CM) has one of the highest response rates across cancers to immune checkpoint blockade (ICB) therapies, but mucosal melanoma (MM) responds poorly to ICB. MM patients have very few effective treatments options, making it critical to understand and improve anti-tumor immunity in these patients. MM is a rare subtype of melanoma, accounting for approximately 1% of all malignant melanoma diagnoses. MM occurs on mucosal surfaces such as nasal, vaginal, and anorectal, which provide a highly unique tumor microenvironment compared to CM arising in the skin. We compared the tumor immune microenvironment between CM and MM by multiplex immunofluorescence and discovered MM has decreased frequency of infiltrating immune cells. Using RNA sequencing, we investigated intra-tumoral differences in global gene expression between CM and MM that might explain the lack of immune cell infiltration and ICB response in MM. Compared to CM, MM had decreased expression of numerous innate immune genes in the RIG-I pathogen-sensing pathway. The RIG-I pathway produces an inflammatory response to destroy foreign pathogens, but is also important for ICB sensitivity and anti-tumor immunity in CM. Studies in CM demonstrate the RIG-I pathway enhances antigen presentation and promotes a favorable immune cell profile in the tumor microenvironment. Interestingly, the tumor microbiome, which is vastly different between CM and MM, has been shown to regulate the RIG-I pathway. We measured total fungal and bacterial load in MM and CM primary tumors and found increased levels of both bacteria and fungi in MM compared to CM. This raises the possibility that microbiome-mediated suppression of the RIG-I pathway underlies poor anti-tumor immunity and ICB response in MM, and that re-activation of this pathway may be a novel therapeutic strategy for overcoming ICB resistance in MM patients. Direct RIG-I agonists are still in clinical development, but FDA-approved hypomethylating agents, particularly 5’ aza-deoxycytidine (decitabine), can activate the RIG-I pathway and improve anti-tumor immunity by increasing the expression of RIG-I pathway activating genes, endogenous RNA retroviruses, tumor antigens, and natural killer (NK) cell ligands. We treated MM cell lines with decitabine and observed strong induction of RIG-I pathway genes, NK ligands, and tumor antigens. In conclusion, we have identified the loss of intra-tumoral RIG-I signaling as a potential microbiome-mediated mechanism underlying the poor tumor immune microenvironment and ICB response in MM. Combining decitabine, which is FDA-approved and now available orally, with ICB represents a novel treatment strategy for these difficult to treat MM patients that can be rapidly translated into the clinic. Citation Format: Morgan MacBeth, Richard Tobin, Robert Van Gulick, Martin D. McCarter, William A. Robinson, Kasey L. Couts. Loss of intra-tumoral RIG-I immune signaling is a potential microbiome-mediated mechanism underlying poor anti-tumor immunity and immunotherapy resistance in mucosal melanoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO048.

Subungual melanoma (SUM) is a type of malignant melanoma that arises beneath the nails of the hands and feet. Subungual melanomas represent a small subset of melanoma patients and have not been well characterized by current molecular techniques. In most studies they have been included in the category of acral melanoma (AM), but there are numerous reasons to believe that they may be different. New effective melanoma treatments rely on both clinical and molecular data to select therapy. In this study, we reviewed characteristics in 29 patients with subungual melanomas seen at our institution in an attempt to provide better understanding and treatment. The median age was 56, almost equally distributed between males and females, with a higher percentage of non-Caucasians than seen in cutaneous melanoma. The most common sites were the thumb (28%), big toe (21%), and index finger (17%). Most were deep at diagnosis (mean Breslow depth 4.21 mm), and 72% had, or developed, metastases and responded poorly to therapy of all kinds. In 12 of the 29 cases, molecular testing via targeted sequencing through Foundation Medicine was done on either a primary or metastatic lesion. These 12 cases were compared to 20 cases of AM seen at our institution. One BRAF mutation was found (1/12, 4%) in SUM, whereas BRAF mutations occurred in about 20% of patients with AM. No patients with SUM had an NRAS mutation, compared to a 45% mutation rate in AM. Two SUM patients had KRAS mutations (2/12, 17%), whereas no patients with AM had a KRAS mutation. Three SUM patients had mutations in KIT (3/12, 25%) compared to one (1/20, 5%) in AM. In addition, 3 patient tumors had a recurrent variant (K587R) in the tuberous sclerosis related gene TSC-1, which has not been described in patients with AM. While our profile of subungual melanoma has some similarities with non-subungual acral melanomas, the high number of KRAS, KIT and TSC1 mutations and lack of BRAF and NRAS mutations suggests that these melanoma may have unique characteristics, different causation, and need specific therapy different from acral melanomas. Citation Format: Blair N. Holman, Robert J. Van Gulick, Carol Amato, Kasey Couts, William A. Robinson. Subungual melanoma: It may be a distinct entity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5431.

Treatment options for melanoma have progressed in recent years, with the rise of targeted therapy and immunotherapy. Options are still limited for patients that are BRAF wildtype, treatment refractory, and patients with non-sun exposed melanoma subtypes that typically do not respond to standard therapies. Therefore, it is necessary to explore other biological processes that may provide new therapeutic approaches. One of most appealing is the BCL-2 family of apoptotic/anti-apoptotic system that is effective in leukemias, with BH3 mimetics venetoclax alone or in combination with the hypomethylating agent 5-azacitidine. We examined similar combinations on the group of eleven patient-derived and commercially available melanoma cell lines. The BH3 mimetics we tested include MCL1 inhibitors (S63845, AMG 176, AZD5991), an inhibitor of BCL2, BCLXL, and BCLW (navitoclax/ABT-263), a BCL2 inhibitor (venotoclax/ABT-199), and a BCLXL inhibitor (A1331852). Our data showed that treatments with MCL1 inhibitors plus 5-azacitidine are effective in reducing melanoma cell viability. S63845 was the most potent compound when combined with 5-azacitidine, with nine out of eleven (~80%) melanoma cell lines achieving less than 50% viability at the highest dose. There was an overall weaker response to treatment with 5-azacitidine in combination with ABT-263 or A1331852, with only 54% and 45% of cell lines responding at the highest dose, respectively. Response to ABT-199 with 5-Azacitidine was highly limited, 18% of cell lines responded at the highest concentration. Our data demonstrate that treatment with S63845 in combination with 5-azacitidine is highly effective in cell lines from a variety of melanoma subtypes, including the rare uveal and mucosal subtypes. In vivo and mechanistic experiments are planned. The novel combination of the MCL1 inhibitor S63845 and 5-azacitidine may be a promising alternative therapeutic target in melanoma. Citation Format: Chiara Dart, Nabanita Mukherjee, Carol Amato, Robert J. Van Gulick, Morgan MacBeth, Kasey Couts, Jacqueline Turner, Stacey Bagby, Mayumi Fujita, William Robinson, Yiqun Shellman. The therapeutic potential of 5-Azacitidine plus various BH3 mimetics in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1805.

John Searle’s ‘Chinese room’ argument aims to refute ‘strong AI’ (artificial intelligence), the view that instantiating a computer program is sufficient for having contentful mental states. Imagine a program that produces conversationally appropriate Chinese responses to Chinese utterances. Suppose Searle, who understands no Chinese, sits in a room and is passed slips of paper bearing strings of shapes which, unbeknown to him, are Chinese sentences. Searle performs the formal manipulations of the program and passes back slips bearing conversationally appropriate Chinese responses. Searle seems to instantiate the program, but understands no Chinese. So, Searle concludes, strong AI is false.

Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.

131 Background: Immune-related adverse events (IRAE) occur commonly with immune checkpoint inhibitor therapy for the treatment of cancer, although the specific event and severity can vary widely. Little is known regarding factors that may predict which patients will develop an IRAE. The goal of this study is to identify blood biomarkers predictive of IRAE associated with immune checkpoint inhibitor therapy. Methods: Blood samples collected from patients with melanoma prior to receiving therapy with immune checkpoint inhibitors were obtained from the University of Colorado Skin Cancer Biorepository. Testing for a panel of autoantibodies and cytokines (ANA, CCP 3.1, IL-1 beta, IL-2, IL-6, IL-10, IL-12, IP-10, MCP-1, TNF alpha, IFN alpha 2, IFN gamma) in serum samples from patients who had at least one documented IRAE was performed by Exsera BioLabs. Descriptive statistics were used to evaluate biomarker levels in relation to type, grade, and number of adverse events. Results: Pre-treatment samples from 45 patients were evaluated. Median age was 55; 26 were male and 19 were female. The most common IRAEs were colitis (n = 22), thyroid dysfunction (n = 21), and dermatitis (n = 20). Most IRAEs were grade 2 in severity, and the majority of patients (n = 36) experienced more than 1 IRAE. TNF alpha was elevated in 60% of patient samples, while IFN alpha 2 was elevated in 44%. Borderline ANA was detected in 27% of samples and ANA was positive in 11%. No samples had elevation of IL-2. Between 9% and 18% of samples had elevation of the other immune markers tested (IFN gamma, IL-1 beta, IL-6, IL-10, IL-12, and CCP 3.1). Elevation of TNF alpha and IFN alpha 2 were associated with higher grades of IRAEs. No associations between immune markers and the number or type of adverse events in an individual patient were noted. Results from 15 patients who did not have a documented IRAE on immune checkpoint inhibitor therapy are currently pending to confirm these findings are unique to patients developing IRAE. Conclusions: This preliminary data suggests that baseline elevations of TNF alpha and IFN alpha 2 may predict development of IRAEs with immune checkpoint inhibitor therapy. Results from samples from patients who did not develop an IRAE on therapy will be reported at the meeting.

In “Absent Qualia and the Mind-Body Problem,” Michael Tye (2006) presents an argument by which he claims to show the inconceivability of beings that are functionally equivalent to phenomenally conscious beings but lack any qualia. On that basis, he concludes that qualia can be fully defined in functional terms. The argument does not suffice to establish the claimed results. In particular it does not show that such absent qualia cases are inconceivable. Tye’s argument relies on a principle P according to which the exchange of isomorphic states between functionally equivalent systems will preserve their equivalence. If they were functionally equivalent before the exchange, they will also be so after. Consideration of the contextual nature of realization shows that Principle P is not a general truth as Tye claims, and his argument against the possibility of absent qualia thus fails.

I begin with a basic account of teleo-pragmatic functionalism and its main features. I then discuss what that view implies about the nature of cognition, theories and understanding and thus about the limits on our ability to explain the mental and its relation to the non-mental. I show that teleo-pragmatic functionalism leads naturally to a version of non-reductive physicalism that combines theoretical pluralism with a strongly contextualist and pragmatic view of theories and models. Though non-reductionist at the theoretical and conceptual level, the view is nonetheless thoroughly and robustly physicalist in its ontology.

Several concepts used in the area of consciousness and cognition are discussed. There are five distinguished types of creature consciousness. An organism may be said to be conscious is it can sense and perceive its environment and has the capacity to respond appropriately. A second sense of creature consciousness requires not merely the capacity to sense or perceive, but the current active use of those capacities. Another notion of creature consciousness requires that organisms be not only aware but also self-aware. Self-awareness comes in degrees and varies along multiple dimensions. The conscious creatures might be defined as those that have an experiential life. Organisms are sometimes said to be conscious of various items or objects. Consciousness in this sense is understood as an intentional relation between the organism and some object or item of which it is aware. The conscious states might be regarded as those that have phenomenal properties or phenomenal character. The representationalist theories claim that conscious states have no mental properties other than their representational properties. Higher-order theories analyze consciousness as a form of self-awareness. Higher-order theories come in several forms. Some treat the requisite higher-order states as perception-like, and thus the process of generating such states is a kind of inner perception or perhaps introspection. The intermediate level representation model focuses on the contents of conscious experience.

L'A. souligne le manque de clarte de l'article precedent intitule «Attitudes as Nonentities». Il critique en particulier l'association rapide qu'y etablit L. Backer entre le presuppose de l'explication causale des croyances, definies comme etats du cerveau, et l'attitude commune qu'elle designe par l'expression point de vue standard. Dans l'article suivant intitule « Reply to Gulick», L. Baker reaffirme ses raisons de rejeter le point de vue standard et de croire que la personne, et non le cerveau, est la porteuse permiere des croyances

As I sit at my desk on a warm and sunny day, I begin to desire a cold drink. Because I believe I can get cold drinking water from the fountain in the hallway I leave my office and go down to the fountain where I satisfy my thirst. Having done so, I return to my office. It's a boring story, but one that illustrates the common sense view that intentional states, such as beliefs and desires, cause behaviors and do so because of their intentional content. Had I not desired a cold drink or not believed that the fountain would provide cold water, I would not have acted as I did. However, even if a causal story about intentional states is implicit in common sense and not everyone agrees it is (Dennett 1987, Bennett 1990) that story need not be true. Many reasons might be found to reject it. One could be an anti-realist of one sort or another about propositional attitudes; if there really are no beliefs or desires then obviously any story that appeals to them as causes must be false. According to the neuro-scientific eliminativists (P. M. Churchland, 1981; P. S. Churchland 1986), brain science will show us that the real causes of human behavior are so unlike beliefs and desires that propositional attitudes will join phlogiston and caloric in the dustbin of mistaken theoretical posits. One could also take an instrumentalist or quasi-realist view of propositional attitudes by allowing that statements about beliefs and desires can be literally true, but holding that their truth consists entirely in facts about patterns of actual and counterfac tual behavior (Dennett 1987, 1991). On such a view, belief and desire talk makes no reference to internal causes of behavior or to any states or events below the personal level (i.e., below the level of facts about the whole person and her behavior). Eliminativists and instrumentalists are alike in denying that there are any beliefs or desires that act as causes of behavior; the success of either version of anti-realism would suffice to refute the common sense causal story. However, defeating anti-realism would not conversely suffice to save the causal story. Showing that there really are propositional attitudes and that they are among the causes of our behavior would not vindicate

Functionalism at its core is the thesis that minds and mental kinds are to be understood in terms of the roles or functions that specific states and processes play within suitably organized systems. From a functionalist perspective, minds differ from non-minds not in any distinctive substance or fundamental substrate, but in their systemic organization and the roles played by their parts and sub-parts within it. A minded system is simply one that is organized in the right sort of way, though just which ways those are is a difficult and disputed matter. Functionalists classify states or processes largely, if not solely, in terms of the relevant roles or functions that they play in some such system.

Few arguments in the recent philosophy of mind have generated as much discussion or controversy as Frank Jackson's Knowledge Argument (KA), and none has had a more surprising history. Having offered the KA in 1983 and ably defended it for fifteen years against a wide variety of objections, Jackson did an about-face in 1998 and disavowed it. His rejection of the argument is essentially coupled with the acceptance of another controversial if widely held view, namely the Representational Theory of Consciousness or at least of Conscious Sensory Experience (RTS), which he regards as the sole means to defeat the KA and avoid the cognitive illusion that generates its intuitive appeal. This chapter begins by briefly reviewing objections to the KA. It considers where, if anywhere, Jackson's own present critical view fits in the logical geography of options. It then turns to the question of whether the RTS is in fact either necessary or sufficient for refuting the KA.

The mind–body problem is the problem of explaining the relation between the mental and the physical, especially the question of whether the mind is something over and above the physical or just a special part of it. Keywords: dualism; Cartesian; consciousness; physicalism; supervenience; panpsychism; dual-aspect theories

The instrumental model offered by Müller & Schumann (M&S) is broadened to apply not only to drugs, but also to other methods of self-control, including the use of mental constructs to produce adaptive changes in behavior with the possibility of synergistic interactions between various instruments.

The reflectance types that Byrne & Hilbert identify with colors count as types only in a way that is more dependent on, and more relative to color perceivers, than their account suggests. Their account of perceptual content may be overly focused on input conditions and distal causes.

One can support O'Regan & Noë's (O&N's) commitment to the active nature of vision and the importance of sensorimotor contingencies without joining them in rejecting any significant role for neurally realized visual representations in the process.