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Funded Research

Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma

Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma

Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma

Raquel Buj, PhD

Mentor Katherine Aird, PhD; John Kirkwood, MD
Award Type Career Development Award
Institution University of Pittsburgh

 

About 40% of melanoma patients have decreased p16, a tumor suppressor protein that inhibits cell proliferation. However, our laboratory and others have found that p16 can regulate other processes besides cell proliferation. Among them, recent indirect evidence suggests that loss of p16 is linked with resistance to immune checkpoint blockade (ICB) therapies, a current standard-of-care for melanoma patients. However, no study has directly demonstrated this relationship nor investigated a molecular reason. Understanding this link is critical to design efficient therapeutic regimens for the large subset of melanoma patients with decreased p16.

Our preliminary data using mouse models has shown for the first time, and in a direct manner, that melanoma tumors with decreased p16 are resistant to ICB therapies. Comprehensive analysis of these mouse tumors, as well as human melanoma tumors, showed that melanoma with decreased p16 increases the secretion of a protein called IGFBP-2. In some cancer models, IGFBP-2 has been shown to modify macrophages. Macrophages are a cell type that reside inside the tumor to help the body’s immune system fight tumor progression. Interestingly, we found that both human and mouse tumors with decreased p16 accumulate a specific type of macrophage, called alternatively-activated macrophages, that decreases the ability of the immune system to fight and can promote ICB resistance. Therefore, we think that increased IGFBP-2 in melanomas with decreased p16 promotes the observed ICB resistance. In this proposal, we aim to investigate whether limiting IGFBP-2 in melanomas with decreased p16 will avoid alternatively-activated macrophages accumulation and hence resensitize these tumors to ICB therapies.

Successful completion of these studies will improve the treatment for melanoma patients with decreased p16 (~40%) who are likely resistant to current standard-of-care ICB therapies.

Targeting Melanoma-Intrinsic STING signaling to Restore Antitumor Immunity

Targeting Melanoma-Intrinsic STING signaling to Restore Antitumor Immunity

Targeting Melanoma-Intrinsic STING signaling to Restore Antitumor Immunity

Rana Falahat, PhD

Mentor James Mule, PhD
Award Type Career Development Award
Institution Moffitt Cancer Center

 

Adoptive cell therapy (ACT) using naturally occurring tumor-infiltrating lymphocytes (TIL) can mediate durable tumor regressions and, in some cases, cure in patients with metastatic melanoma. However, its efficacy remains highly variable and patient-specific. Two most likely reasons why some patients do not respond favorably to this therapy include: 1) lack or loss of signals in tumor cells that make them visible to immune T cells and 2) lack or insufficient infiltration and presence of tumor-fighting T cells within tumors. An important signaling pathway that contributes to interactions between tumor cells and immune T cells is the type I interferon signaling pathway. The type I interferon pathway increases expression of molecules that allow tumor cells to be recognized and killed by immune T cells. One of the key molecules in the type I interferon signaling pathway is stimulator of interferon genes (STING). When activated, STING induces expression of molecules called T cell-homing chemokines that are critical for the recruitment and localization of immune T cells within tumors. We have recently discovered an important loss and defect in STING gene expression in melanoma cells which helps them to evade from immune T cell detection and destruction. We have also shown that this loss of STING expression in melanoma cells can be reversed with a clinically available demethylating drug. In this proposal, we will test a series of STING-activating and -restoring strategies to generate and empower autologous TIL expansion and function in mouse models of melanoma. We predict the findings from these studies will provide opportunities for future development of more effective T cell–based immunotherapies in patients with metastatic melanoma who do not currently benefit from these interventions.

Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Exploiting Metabolic Vulnerabilities of Macrophages for Melanoma Treatment

Stanley (Ching-Cheng) Huang, PhD

Mentor Alex Huang, MD, PhD
Award Type Career Development Award
Institution Case Western Reserve University

 

While significant progress has been made in developing new therapeutics to control melanoma, the promising clinical outcomes of immune checkpoint inhibitors have drastically shifted the paradigm of cancer treatment. However, a high rate of primary resistance impedes the efficacy of checkpoint inhibitor treatments. Therefore, there is an urgent need for a more detailed understanding of how immune cells govern melanoma progression, as it provides a critical foundation for developing novel interventions and targets to enhance current melanoma immunotherapies. Macrophages are the frontline soldiers of the immune system. Their role is to reduce pathogenic insults and alert other immune cells to an external attack. Macrophages need to adopt different types of defense modes (or armors) in order to carry out their diverse functions, from combating the different types of invading pathogens to fighting cancer. These modes are referred to as pro-inflammatory M1 and anti-inflammatory M2. It was recently found that changes in cell-intrinsic and extrinsic metabolism can alter the immunity mode adapted by macrophages to respond to the pathogenesis of cancer but the mechanism underlying decision-making is still elusive. We propose that an important metabolic network called “serine one-carbon metabolism” plays a crucial role in M2 macrophages, and can be controlled to win the fight against melanoma. By investigating this and the different ‘forces’ that shape macrophage immunity, we hope to understand how macrophages decide to choose their armor to eliminate cancer. The ultimate aim is the ability to harness macrophage immunity to develop new and effective immunotherapies for melanoma.

Therapeutic Combinations against Melanoma Brain Metastases

Therapeutic Combinations against Melanoma Brain Metastases

Therapeutic Combinations against Melanoma Brain Metastases

Sixue Liu, PhD

Mentor Roger Lo, MD, PhD
Award Type Career Development Award
Institution University of California, Los Angeles

 

Melanoma is a lethal form of skin cancer because it has a high propensity to metastasize, especially to the brain (often causing death). Compounding this problem is the observation that melanoma brain metastasis is relatively therapy resistant. We proposed a novel sequential-combinatorial therapy aimed at suppressing melanoma brain metastasis and designed studies (using novel molecular technologies) to understand the underlying mechanisms in order to accelerate clinical translation of our findings.

Pilot Trial of Tumor Infiltrating Lymphocytes for Melanoma Brain Metastasis

Pilot Trial of Tumor Infiltrating Lymphocytes for Melanoma Brain Metastasis

Pilot Trial of Tumor Infiltrating Lymphocytes for Melanoma Brain Metastasis

Allison Betof Warner, MD, PhD

Mentor Jedd Wolchok, MD, PhD; Mike Postow, MD
Award Type Career Development Award
Institution Memorial Sloan Kettering Cancer Center

 

Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced disease. Modern systemic therapies do not adequately control brain metastases. For patients whose disease has progressed on standard immunotherapy and targeted therapy (if appropriate), there are no approved treatments that have demonstrated efficacy against MBM. Little is known about the mechanisms of MBM growth or treatment resistance. Few new treatment approaches are on the horizon, as patients with MBM are frequently excluded from clinical trials.

A new type of immunotherapy using tumor infiltrating lymphocytes (TIL) has demonstrated efficacy in advanced melanoma. Lifileucel, an drug made from patients’ own T cells, was recently shown to be safe and effective in patients with melanoma that has progressed on standard immunotherapy and targeted therapy. These promising preliminary results have been met with great enthusiasm for TIL therapy as a potential approach for melanoma that has progressed after immunotherapy treatment. Follow-up studies are ongoing with expectation of FDA approval within the next year. Participants with active MBM were excluded from lifileucel trials to date, so the feasibility and safety of lifileucel are unknown in this population. Only a small number of patients with active MBM have been treated with any type of TIL therapy. To address the critical need for therapeutic options and deeper biological understanding of MBM, we propose a pilot study to rigorously define the feasibility of treating patients with MBM with lifileucel.

This will be the first study to evaluate lifileucel for active MBM. Establishing feasibility and safety of this approach could rapidly lead to larger phase II efficacy and combination trials, which have the potential to change treatment paradigms and improve outcomes from this dreaded complication of melanoma. We have proposed extensive correlative analyses using blood and cerebrospinal fluid (CSF) to enhance our mechanistic understanding of the biology driving the growth and treatment resistance of brain metastases and what changes occur during the course of cell therapy treatment.

Treatment of MBM, particularly after progression on standard immunotherapy treatments, is one of the most urgent unmet needs in the therapy of melanoma. Successful completion of this trial and the correlative studies could improve clinical management of this morbid complication of melanoma and inform decision-making for further cellular therapy approaches in MBM and other cancers that metastasize to the brain.