Cutaneous Lymphoma Foundation FORUM 2023 Issue 1 - Research Edition Advance research and patient care focused on tackling the most important unmet needs of people with cutaneous lymphoma From the President and the Chief Executive Officer. ............................................................. 3 2022 Catalyst Research Grants...........................4 2021 Catalyst Research Grants...........................6 2022 Young Investigator Awards - ASH.........8 2022 Young Investigator Award - SID...........11 Help Advance Research............................Back Cutaneous Lymphoma Foundation CUTANEOUS LYMPHOMA RESEARCH As you dive into the following pages and the incredible research done by the recipients of this year's Young Investigator Awards and Catalyst Grants, we hope you will take great pride in our investment on your behalf. This year marks the beginning of a new strategic plan, which we are finalizing and will share soon. The Foundation's Board of Directors and Research Advisory Council continue to look toward the future to ensure that we make the most of our donors' funding and how we represent your voice in research - ultimately providing the most significant impact in advancing cutaneous lymphoma care. Strategy 3 of the plan, is written as: advance research and patient care focused on tackling the most important unmet needs of people with cutaneous lymphoma. As we work to achieve this strategic objective, we continue to seek opportunities to support the pillars outlined in the Cutaneous Lymphoma Research Roadmap while adding one more, Pillar 4, Quality of Life. The Foundation has always had a strong interest in helping the broader community understand the impact of cutaneous lymphomas on people living with it. Dating back to the early 2000s, we funded the very first quality-of-life study in cutaneous lymphoma with Dr. Marie-France Demierre. We continue to be a visible participant across all areas addressing access, drug development, and clinical advancement, serving as a patient opinion leader. More and more, a top priority among clinicians and drug manufacturers, and a requirement by policymakers and regulators, is including the patient's experience. This resulted in the addition of Pillar 4: Quality of Life - gathering patient-reported lived experience on how cutaneous lymphoma impacts their life. We hope you are excited about how far we have come - investing nearly $900,000, funding 19 research projects, and supporting 33 young researchers - and the vision of hope for the future to meet the most critical needs of people impacted by cutaneous lymphoma.
2 CUTANEOUS LYMPHOMA FOUNDATION The newsletter of the Cutaneous Lymphoma Foundation ALL RIGHTS RESERVED FORUM Cutaneous Lymphoma Foundation PO Box 969 Warren, MI 48090 Telephone: (248) 644-9014 Email: info@clfoundation.org www.clfoundation.org Forum is published by the Cutaneous Lymphoma Foundation. Editor: Autumn Lintz Layout & Design: Deb Van Zegeren Disclaimer The Cutaneous Lymphoma Foundation does not endorse any drugs, treatments or products reported in this newsletter. Information is provided for informational purposes only. Because the symptoms and severity of cutaneous lymphoma vary among individuals, the Cutaneous Lymphoma Foundation recommends that all drugs and treatments be discussed with the reader’s physician(s) for proper evaluation, treatment and medical care. What Is Cutaneous Lymphoma? Cutaneous lymphomas are cancers of lymphocytes (white blood cells) that primarily involve the skin. Classification is based on lymphocyte type: B-lymphocytes (B-cell) or T-lymphocytes (T-cell). Cutaneous T-cell lymphoma (CTCL) is the most common type of cutaneous lymphoma that typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. Progression from limited skin involvement is variable and may be accompanied by tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood, and internal organs. BOARD OF DIRECTORS OFFICERS Laurel Carlson President David Elefant Vice President Jeff Ward Treasurer Marianne Tawa, RN, MSN, ANP Secretary DIRECTORS Steven Horwitz, MD Director Youn Kim, MD Director Michael W. Young Director Susan Thornton Chief Executive Officer RESEARCH ADVISORY COUNCIL Christine Eischen, PhD (Co-Chair) Thomas Jefferson University Pierluigi Porcu, MD (Co-Chair) Thomas Jefferson University Jaehyuk Choi, MD, PhD Northwestern University Alejandro Gru, MD University of Virginia Bradley Haverkos, MD, MPH University of Colorado Michael Khodadoust, MD, PhD Stanford University Anjali Mishra, PhD Sidney Kimmel Cancer Center Alison Moskowitz, MD Memorial Sloan Kettering Cancer Center MEDICAL ADVISORY COUNCIL Michi Shinohara, MD (Chair) University of Washington Wei Ai, MD University of California San Francisco Kim Bohjanen, MD University of Minnesota Francine Foss, MD Yale University Richard Hoppe, MD Stanford Cancer Center Erick Lansigan, MD Dartmouth-Hitchcock Medical Center Cecilia Larocca, MD Dana-Farber/Brigham and Women’s Cancer Center Leora Lowenthal, LICSW, OSW-C, MPA Beth Israel Deaconess Medical Center Sue McCann, MSN, RN, DNC University of Pittsburgh Amy Musiek, MD Washington University School of Medicine Steve Rosen, MD, FACP City of Hope Debjani Sahni, MD Boston University Jasmine Zain, MD City of Hope MEDICAL ADVISORY COUNCIL EMERITUS ADVISORS Madeleine Duvic, MD University of Texas MD Anderson Lars French, MD University Hospital Zurich Ellen Kim, MD University of Pennsylvania Robert Knobler, MD Medical University of Vienna Liliane LaRoche, MD Hospital Avicenna David Ramsay, MD New York University School of Medicine Alain Rook, MD University of Pennsylvania Martin Weinstock, MD, PhD Brown University Sean Whittaker, MRCP Guy's and St. Thomas' Hospital STAFF Holly Priebe Chief Operating and Financial Officer Autumn Lintz Education Manager Deb Van Zegeren Special Projects Manager Susette Arnot Programs and Services Assistant CUTANEOUS LYMPHOMA FOUNDATION Cutaneous Lymphoma Foundation is a 501(c)(3) non-profit organization. Donations are tax deductible to the extent allowed by law. The Cutaneous Lymphoma Foundation’s patient educational newsletter, Forum, has been made possible in part thanks to the following generous supporters:
ISSUE 1- RESEARCH EDITION, 2023 Susan Thornton Somewhere in the world, someone in a lab is working to figure out answers. Paraphrased from a presentation by cutaneous lymphoma specialist, Dr. John Zic, Vanderbilt University Hospital. When discussing research in cutaneous lymphoma, we love to share the above quote from Dr. John Zic. It is true. As your representative at the various scientific and medical meetings worldwide, we have the privilege of listening to the outcomes of work being done in labs and clinics by incredibly dedicated people. The treatment toolbox and methods of managing the wide range of cutaneous lymphomas come from this intense work in the petri dish and every day in the clinic. This Forum focuses on research projects we have funded. It gives a small glimpse into the work necessary to learn more about this complex group of diseases. It is a pleasure to share with you the wide variety of projects on the following pages, all of which are valuable pieces to putting together the cutaneous lymphoma puzzle. While you may not have a research or scientific background, we hope the brief articles are informative and inspiring. For all of us living with cutaneous lymphoma, know that there is someone in a lab with the light on working hard on your behalf somewhere in the world. Sometimes progress is painfully slow and meticulous. Know that every nuance uncovered in a research project helps to add another piece to the puzzle. Progress is happening! Enjoy the updates, and know that there is always hope! FROM THE BOARD PRESIDENT AND CHIEF EXECUTIVE OFFICER Laurel Carlson, Board President; Susan Thornton, CEO Laurel Carlson 3 TOGETHER AGAIN! 2-DAY PATIENT CONFERENCE FRIDAY EVENING, APRIL 21, 2023 - SUNDAY NOON, APRIL 23, 2023 Learn! Connect! Celebrate! The annual 2-Day Patient Conference is open to anyone affected by cutaneous lymphoma. Regardless of where you are in your journey, the conference is an opportunity to learn more about living with cutaneous lymphoma. Visit www.clfoundation.org/Bethesda2023 or use the QR code to learn more.
4 CUTANEOUS LYMPHOMA FOUNDATION 2022 CATALYST RESEARCH GRANT RECIPIENTS QUALITY OF LIFE IN PATIENTS WITH CUTANEOUS T-CELL LYMPHOMA: VALIDATION OF A NOVEL QUALITY OF LIFE INSTRUMENT Neha Mehta-Shah, MD Associate Professor of Medicine Department of Medicine Division of Oncology Washington University in St. Louis Neha Akkad, MD Internal Medicine Resident Post-grad year 3 Department of Medicine Washington University in St. Louis Cutaneous T-cell lymphoma (CTCL) is a rare cancer that mainly affects the skin, blood, and lymph nodes. It is a particularly unique cancer in that it causes significantly debilitating symptoms. Studies have shown that CTCL has a negative impact on patient quality of life even more so than patients with other skin conditions requiring similar treatment. We have found this is due to its unique symptoms, treatments, and psychosocial burden on the people affected. Given this, it is important to have a way to evaluate CTCL patients’ quality of life in a meaningful, comprehensive, and disease specific manner. Though there are many surveys available to evaluate quality of life, we have found that the existing surveys do not encompass all themes important to CTCL patients, particularly for those with advanced stage disease. This can be seen in the accompanying table. We have therefore set out to create a new survey that fully encompasses all themes important to CTCL patients, that will be made employing the voice of the patients themselves. Thus far, we have conducted interviews with CTCL patients treated at Washington University in St. Louis and analyzed what themes are most important to their quality of life. From this data we have created a new survey that intentionally has multiple questions surrounding certain themes so we can trial different ways to word similar themes, and see how different patients answer them. Since writing this new survey, we have done extensive cognitive interviews with a small group of patients in order to discuss the wording, format, answer choices, and themes included in our survey, similar to a focus group. During these meetings, we received feedback on how to make the survey clear, easier to understand, and comprehensive. They were given the opportunity to tell us which questions were more or less relevant, as well as give input if there were themes that they felt were not fully covered. From the excellent feedback we received from our patients, we have re-written our new survey. One notable observation that came up repeatedly was how different the patient experience with quality of life was in patients with early versus late stage disease. Patients with later stage disease expressed how much their quality of life has been negatively affected in all domains CUTANEOUS LYMPHOMA
5 ISSUE 1- RESEARCH EDITION, 2023 RESEARCH GRANT UPDATES including symptom burden, sleep, hopelessness, etc. This further highlights the importance of including patients in all stages of disease in survey creation, something that has not been done in prior survey creation. Our next step will be to distribute our survey along with other previously existing surveys in order to analyze its performance. From this data, we will be able to further consolidate the questions in our survey so only the best and best combination of questions is used in our final product. Our ultimate goal is to distribute this survey to multiple institutions in order to ensure our survey holds up in other patient populations besides our own. Eventually, we hope that this survey could be used as an additional tool to accurately evaluate, and thereby properly address, quality of life specifically in patients with CTCL, as well as be used in clinical trials to better understand the impact of treatment on patients. As reported by Dr. Tegla in a recent interview with the Foundation, the aim of his research project is investigating the therapeutic potential of atovaquone as a novel agent for the treatment of CTCL. Atovaquone is an FDA-approved antimicrobial that has been used for over 20 years for the treatment or prevention of malaria, PCP pneumonia, toxoplasmosis or babesiosis. It is a safe drug with a good track record. Our preliminary data shows that the atovaquone effectively blocks the proliferation of malignant CTCL cells and specifically inhibits the viability of the malignant CTCL cells with little impact on the normal T-cell counterparts. The hypothesis of this study is that atovaquone blocks a specific vulnerability of the metabolically rewired malignant cells. The aims of Dr. Tegla’s project are to define the metabolic changes that are induced by atovaquone treatment to help determine what this underlying vulnerability is, and to determine the mechanism of action of atovaquone by using a genome-wide CRISPR cast screen aimed at identifying key effector genes. Atovaquone could become a new therapeutic option for the treatment of CTCL because of its current FDA-approved status. Because it's a safe drug, it could easily benefit patients with early stage disease where the whole treatment goal is to minimize interventions while maximizing quality of life. At the same time, it could benefit patients with advanced stage disease where the goal of treatment is to maximize responses and duration of remissions. In either situation, atovaquone could easily be combined with the standard of care to help improve outcomes with minimal safety concerns. In the long term, this project would help identify novel therapeutic targets in CTCL and perhaps other malignancies that share similar biology. Based on our preliminary findings, atovaquone targets CTCL in a novel and unique way. Elucidating its mechanism of action could lead to new therapeutic strategies in CTCLs and potentially have a broader impact on other malignancies that have similar biologies. To view Dr. Tegla’s full interview, visit https://youtu.be/z_UwhRmsRVc Cosmin Tegla, MD Assistant Professor Department of Medicine, Division of Hematology and Oncology NYU Grossman School of Medicine REPURPOSING ATOVAQUONE, AN FDA-APPROVED ANTIMICROBIAL, FOR THE TREATMENT OF CUTANEOUS T-CELL LYMPHOMA
6 CUTANEOUS LYMPHOMA FOUNDATION Sézary syndrome (SS) is an aggressive primary cutaneous T-cell lymphoma characterized by malignant cells circulating in the blood and progressive impairment of the immune response. No curative treatments are available so far. Immunotherapy seems to be a promising avenue to achieve longterm disease control; however, relapses are frequent with only few patients achieving long-term remissions. This is due to the ability of tumor cells to exploit different strategies to escape the host’s immune responses. A key hallmark of SS is severe progressive T cell immunodeficiency, which contributes to increased risk of infections that are the most prevalent cause of death in patients with advanced disease. What is coming into focus is that the malignant T cell is a key driver of immunosuppression, reshaping the cutaneous microenvironment and broadly impairing cellular immunity, which is needed for an effective anti-tumor response. Understanding how tumor cells escape from immune surveillance and how past and emerging therapies can modulate the immune system is the starting point for the development of more effective multimodal and combination therapies. Emerging as a relatively new immune checkpoint is the production and accumulation of immunosuppressive metabolites in the tumor microenvironment. Project objective: To investigate whether the sequential activity of CD39 and CD73 ectoenzymes - highly expressed by malignant T cells as well as by immune cells and vasculature – might scavenge ATP released by apoptotic cells and generates immunosuppressive adenosine in the tumor microenvironment thus contributing to tumor escape from immune response and immune dysfunctions in patients with SS. Milestones: i) In our study we demonstrated aberrant expression of two proteins (namely, CD39 or CD73) in malignant T cells circulating in the blood and infiltrating the skin in SS patients. Both proteins are key players in the generation of immunosuppressive adenosine from ATP, an energy-carrying molecule released from dying and stressed cells. Adenosine is a potent immunosuppressive mediator promoting tumor intrinsic or therapy-induced immune escape by various mechanisms. ii) The expression of these two molecules allowed us to identify two subgroups of patients with high expression of CD39 or CD73, respectively. Patients showing high CD39 expression proved to be characterized by a highly immunosuppresPietro Quaglino, MD Associate Professor Dermatologic Clinic, Dept Medical Sciences University of Turino, Italy MECHANISTIC INSIGHTS INTO THE CD39/CD73 ADENOSINERGIC IMMUNO-SUPPRESSIVE AXIS IN PATIENTS WITH SÉZARY SYNDROME: ASSOCIATION WITH DISEASE COURSE AND TREATMENT RESPONSE 2021 CATALYST RESEARCH GRANT RECIPIENTS CUTANEOUS LYMPHOMA
7 ISSUE 1- RESEARCH EDITION, 2023 H-1PV-INDUCED ONCOLYSIS AND TUMOR MICROENVIRONMENT IMMUNE STIMULATION IN A NOVEL HETEROTYPIC SPHEROID MODEL OF CUTANEOUS T-CELL LYMPHOMA The project focused on a novel approach to cutaneous lymphoma treatment, namely the use of a “good” (so-called oncolytic) virus that is able to kill cancer while sparing healthy cells. The oncolytic parvovirus H-1 (H-1PV) has long been shown to be a promising therapeutic agent against a variety of solid tumors such as glioma and pancreatic cancer. However, H-1PV potential to become a new weapon in the fight against cutaneous lymphoma was never studied before, and was first made possible through the Catalyst Research Grant of the Cutaneous Lymphoma Foundation. For the sake of better relevance to patients’ situations, a novel in vitro (spheroid) model was developed, with the aim to reproduce tumor complexity in vivo. Studies in this model led to the generation of first preclinical data that strongly encouraged further research on H-1PV as a candidate drug for the treatment of cutaneous lymphoma. Briefly, while being innocuous for normal blood cells, this oncolytic virus was able to kill cutaneous lymphoma cells and to cause significant shrinkage of lymphoma spheroids. The killing effect – oncolysis - was independent of the expression of cellular pro-survival proteins (Bcl-2), but might be boosted by purinergic receptor (P2X7) activation and signaling. In addition to oncolysis induction, parvovirus infection of tumor cells triggered the release of danger associated molecules (in particular, extracellular adenosine triphosphate) that may alert the immune system of the host to the presence of parvovirus-infected lymphoma cells. Furthermore, when lymphoma spheroids were co-cultured with human peripheral blood cells, H-1PV treatment caused the secretion of inflammatory mediators such as tumor necrosis factor-alpha and increased spheroid infiltration with immune cells. The capacity of the virus to induce efficient immunogenic death of cutaneous lymphoma cells deserves further investigation and holds promise for the development of a novel therapy against this disease. Assia Angelova, PhD Clinical Cooperation Unit Virotherapy German Cancer Research Center sive microenvironment dampening the immune response against the tumor. iii) In experimental conditions recapitulating the situation occurring in vivo, we demonstrated that using specific drugs able to block the functions implemented by CD39 or CD73 thus inhibiting the adenosinergic pathways, has the potential to unleash an immune-mediated anti-tumor response. These findings suggest that modulating cancer-derived adenosine in the tumor microenvironment is an attractive novel therapeutic strategy to limit tumor progression, improve antitumor immune responses and avoid therapy-induced immune deviation. While what will be the most effective therapeutic regimen for SS patients remains unclear, the current trend appears to be combination therapy able to eliminate the disease via effective killing of immunosuppressive tumor cells, coupled with activation and education of the immune system to generate a potent anti-tumor immune response. Through better understanding of various immune modulating pathways, superior combination therapies may be developed, and prolonged remissions realized, eventually improving the quality of life for patients. Additional Research Credits: Ada Funaro, MD, PhD, Department of Medical Sciences, University of Torino, Italy RESEARCH GRANT UPDATES
8 CUTANEOUS LYMPHOMA FOUNDATION Zhen Han, PhD, MD Assistant Research Professor Department of Surgery Beckman Research Institute, City of Hope 2022 YOUNG INVESTIGATOR AWARD RECIPIENTS AMERICAN SOCIETY OF HEMATOLOGY (ASH) ANNUAL MEETING Background Blockade of PD1/PD-L1 (NCT03011814) and CD47/ SIRPα (NCT02890368) have shown promising and durable therapeutic outcomes in cutaneous T-cell lymphoma (CTCL), but resistance and/or relapses are seen in a subset of patients. To improve outcomes of immunotherapy regimens for CTCL patients, we investigated the effects of dual CD47 and PD-L1 blockade as a strategy for targeting both the innate and adaptive immune system. Methods We performed RNA sequencing, gene expression deconvolution (CIBERSORT) and flow cytometry analysis to assess the immune cell composition, and CD47, SIPRα and PD-L1 expression in 45 CTCL patient samples and CTCL cell lines. CTCL specimens at baseline and during treatment with anti-CD47/SIRPα (TTI621) and anti-PD-L1 (durvalumab) were used to analyze immune cell gene expression. We performed functional assays utilizing our macrophage and CTCL cell line culture systems to assess macrophage polarization, phagocytic activity of macrophages against CTCL cells, T cell-mediated cytotoxicity using a chromium release assay, and CTCL cell line proliferation before and after CD47/SIRPα (TTI-621) and anti-PD-L1 antibody (durvalumab) treatment. Results Our data showed that CTCL cells and CTCL cell lines overexpress CD47 and PD-L1 compared with healthy control cells, and overexpression of CD47 and PD-L1 was associated with high MYC expression in CTCL cell lines. CIBERSORT analysis of CTCL samples compared to healthy control indicated that the fraction of M2 tumor-associated macrophages (TAMs) was increased, while M0/1 were significantly lower. Our NanoString data showed decreased M2 genes, immature DC-related genes, the NK cell inhibitory receptor related genes, and up-regulation of M1 genes and the NK cell stimulatory receptors associated genes for CTCL patients after treatment with TTI-621 compared to baseline. In vitro, treatment with TTI-621 increased the phagocytic activity of macrophages against CTCL cells and enhanced CD8+ T-cell-mediated killing. Moreover, TTI-621 synergized with anti-PD-L1 (durvalumab) to reprogram M2-like tumor-associated macrophages to M1-like phenotypes by inhibiting MYC expression. Simultaneous exposure to TTI-621 and anti-PD-L1 inhibited growth of CTCL cell lines more potently than either antibody alone. RNA sequencing analysis indicated these effects were mediated by cell‒death-related pathways, such as apoptosis, autophagy, and necroptosis. Conclusions Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of the immune microenvironment in CTCL and that dual targeting of CD47 and PD-L1 may potentiate anti-tumor responses in CTCL. Additional Research Credits: Xiwei Wu3,4, Yate-Ching Yuan5,6, Hanjun Qin3,4, Chingyu Su1,2, Jasmine Zain7, Oleg E Akilov8, Steven T. Rosen2,7, Mingye Feng2,9, Christiane Querfeld1,2,7,10 Institutions: 1Division of Dermatology, City of Hope, Duarte, CA; 2Beckman Research Institute, City of Hope, Duarte, CA; 3Department of Molecular and Cellular Biology, City of Hope, Duarte, CA; 4Integrative Genomics Core, City of Hope, Duarte, CA; 5Department of Computational Quantitative Medicine, City of Hope, Duarte, CA; 6Translational Bioinformatics, Center for informatics, City of Hope, Duarte, CA; 7Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA; 8Cutaneous Lymphoma Program, Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA; 9Department of Immuno-Oncology, City of Hope, Duarte, CA; 10Department of Pathology, City of Hope, Duarte, CA. BLOCKADE OF THE IMMUNE CHECKPOINT CD47 BY TTI-621 POTENTIATES THE RESPONSE TO ANTI-PD-L1 IN CUTANEOUS T CELL LYMPHOMA CUTANEOUS LYMPHOMA
9 ISSUE 1- RESEARCH EDITION, 2023 CLINICAL CHARACTERISTICS, TREATMENT PATTERNS, AND OUTCOMES OF CYTOTOXIC CUTANEOUS T-CELL LYMPHOMAS Introduction Cytotoxic cutaneous T-cell lymphomas (CCTCLs) are an uncommon group of neoplasms defined by expression of at least one cytotoxic marker (e.g. TIA-1, granzyme B, or perforin). Due to their rarity, comparatively little is known about their presentation and overall course. Here, we present a detailed retrospective experience of patients with CCTCLs, focusing on their clinicopathologic and molecular characteristics, treatment details, and survival outcomes. Methods The Stanford University Cutaneous Lymphoma Database was queried to gather data on patients with CCTCLs seen between 1995-2020, including the following diagnoses: subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous γδ T-cell lymphoma (PCGDTCL), primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECTCL), and unclassified CCTCLs (CCTCL-NOS). Clinical and laboratory data, including clinical suspicion of hemophagocytic syndrome (HPS), were extracted from the electronic medical record. Treatment data were recorded, including use of radiotherapy (RT), pralatrexate, romidepsin, brentuximab vedotin (BV), combination chemotherapy, allogeneic stem cell transplant (allo-SCT), and others. We evaluated time to next treatment (TTNT), calculated as the start date of one line of therapy to the start date of next line of therapy, in addition to overall survival (OS) and factors predictive of outcome. A subset of patients was evaluated with a clinically validated high-throughput sequencing panel for hematopoietic and lymphoid neoplasms (Heme-STAMP) covering 164 genes. Results 46 patients were included: 22 (47.8%) SPTCL, 13 (28.2%) PCGDTCL, 3 (6.5%) PCAECTCL, and 8 (17.3%) CCTCLNOS. Mean age at diagnosis was 55.7 years (range: 14.9 – 87.4). Most patients (87%) presented with generalized skin lesions, while involvement of lymph nodes (22.2%), viscera (8.9%), or bone marrow involvement (3.1%) were uncommon. Clinical suspicion for HPS was noted in 23 (50%) patients. Median lines of therapy received was 2.5 (range: 1-12). Median TTNT (mTTNT) from first-line therapy was 8.5 months, second-line 5.3 months, and third-line 7.8 months. Variation in mTTNT was observed between CCTCL subtypes. In patients with SPTCL, mTTNT from first and second-line therapy were 10.2 and 24.0 months, respectively. In patients with PCGDTCL, mTTNT after first-line therapy was 11.1 months, decreasing sharply thereafter (0.5-3.1 mo. for 2nd-5th lines). Patients with PCAECTCL had short mTTNT of less than 3 months for all lines of treatment. Patients with CCTCL-NOS exhibited more heterogeneity (mTTNT 2.9 – 9.1 mo. for 1st-5th lines). The most commonly used treatments were combination chemotherapy (n=24 instances, mTTNT 7.2 mo.), pralatrexate (n=18, mTTNT 11.6 mo.), romidepsin (n=17, mTTNT 2.4 mo.), RT (n=16, mTTNT 3 mo.), and BV (n=11, mTTNT 3.7 mo.). Median TTNT varied between CCTCL subtypes and was generally longest in patients with SPTCL. 2- and 5-year OS were 73.5% and 64.2%, respectively. Significant differences were observed between CCTCL subtypes (Figure 1 - page 10). Age > 60 was associated with worse survival (2-year OS 42.3 vs. 100%, p < .0001). Extracutaneous involvement was not associated with outcome (2-year OS 60.6 vs. 69.1%, p = 0.5), nor was documented clinical suspicion for HPS (2-year OS 82.2% vs. 64.8%, p = 0.21). Patients undergoing allo-SCT (n = 9) had superior OS (2-year OS 100% vs. 66.1%, p = 0.03) (Figure 2 - page 10). Eric Mou, MD Clinical Assistant Professor Division of Hematology, Oncology, and Blood & Marrow Transplantation The University of Iowa Continued on page 10... RESEARCH GRANT UPDATES
10 CUTANEOUS LYMPHOMA FOUNDATION Thirteen (28.3%) patients had data available from Heme-STAMP testing; every patient who underwent testing had at least one identified mutation. The most frequently occurring somatic mutations included TP53 (n = 3), TERT (n = 3), and JAK1 (n = 3). Conclusions CCTCLs are rare entities with heterogeneous presentation, response to therapy, and survival. Chemotherapy remains an effective treatment, and we identify pralatrexate as a promising single agent option. Allo-SCT offers curative potential in eligible patients. Given wide variation in disease behavior, treatment intensity should be tailored to each individual’s clinical phenotype to optimally balance risk and benefit. Further efforts to define the molecular basis of CCTCLs are urgently needed to aid in the identification of more effective therapies. Figure 1. Overall Survival by CCTCL Subtype Figure 2. Overall Survival by Patients Receiving Allogeneic Transplant Versus Remainder of Cohort Additional Research Credits: Sebastian Fernandez-Pol, MD, PhD3; Shufeng Li, MS4; Youn H. Kim, MD4, and Michael S Khodadoust, MD, PhD1,4. Institutions: 1Division of Oncology, Stanford University, Stanford, CA; 2Division of Hematology, Oncology, and Blood & Marrow Transplantation, The University of Iowa, Iowa City, IA; 3Department of Pathology, Stanford University, Stanford, CA; 4Department of Dermatology, Stanford University, Stanford, CA Continued from pg 9... CUTANEOUS LYMPHOMA
11 ISSUE 1- RESEARCH EDITION, 2023 Cutaneous T cell lymphoma (CTCL) is an incurable cancer; understanding its underlying molecular mechanisms may unlock a cure. In patient samples of CTCL, we observed a significant increase in gene expression of p38β while that of p38α decreased, compared to normal healthy CD4 T cells. This prompted us to further dissect the role of p38β in CTCL to inform the application of small molecule inhibitors that specifically target p38β. Current well-developed small molecule p38 inhibitors target both p38α as well as p38β, as they share ~80% structural similarity. However, multiple clinical trials have shown adverse effects and development of drug resistance when patients with cancer are treated with potent p38 inhibitors alone. Such side effects likely occur because p38α is an essential protein in many cell types; indeed, p38α gene knock-out mice exhibit embryonic lethality. Therefore, any prolonged treatment using p38α inhibition may cause adverse effects. Using Hut78 CTCL cells in which we silenced p38β using lentiviral siRNA, we tested for possible mechanisms of drug resistance that could explain why patients who participated in p38α/β inhibitor clinical trials experience adverse effects. Gene silencing of p38β in Hut78 cells did not decrease cell proliferation; instead, proliferation slightly increased compared to that of WT cells. This aligned with increased IL-17 RA and p38γ which is a driver for cell proliferation in Hut78 cells. Our hypothesis is that p38β-depleted CTCL cells increase survival by elevating the MAPK12NFAT-IL17 signaling pathway axis, which increases proliferation and propagandas inflammation in the surrounding regions resulting in drug resistance and adverse effects. We used confocal immuno-fluorescence microscopy analyses of p38β-depleted Hut78 cells to reveal a novel molecular mechanism, in which depleting p38β offset cytoskeleton formation in the cytosol. This suggests p38β is important for maintaining the shape or frame of CTCL cells, and may explain why CTCL, a malignant T cell infiltrate skin, from which novel revenues of drug development may be invented that are complementary to p38β inhibition. Xu Hannah Zhang, PhD Assistant Research Professor Department of Hematology & Hematologic Cell Transplantation Beckman Research Institute, City of Hope ROLE OF p38β IN CUTANEOUS T CELL LYMPHOMA 2022 YOUNG INVESTIGATOR AWARD RECIPIENT SOCIETY OF INVESTIGATIVE DERMATOLOGY (SID) ANNUAL MEETING Additional Research Credits: Sangkil Nam1 , Jack Hsiang1 , Steven Rosen1 Institutions: 1Beckman Research Institute, City of Hope, Duarte, CA, United States. Subscribe to the Cutaneous Lymphoma Foundation's YouTube channel (CutaneousLymphomaFnd) and follow us on Facebook and LinkedIn. To learn about upcoming events, visit www.clfoundation.org/upcoming-events or scan the QR-code below. DON'T MISS OUT... RESEARCH GRANT UPDATES
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