Peck Symposium 2022 Speakers
Pawel Kalinski, Ph.D.
Professor of Oncology & Chief, Translational Immuno-Oncology, Roswell Park Comprehensive Cancer Center
Pawel Kalinski, Ph.D. is Senior Vice President for Team Science, Chair of Department of Immunology and Chief of Division of Translational Immuno-Oncology at Roswell Park Comprehensive Cancer Center in Buffalo, NY. Dr. Kalinski obtained MD (1991) from the Medical University of Warsaw, Poland, and PhD (Immunology; 1998) from the University of Amsterdam in the Netherlands. Before joining Roswell in 2017, Dr. Kalinski was a tenured Professor of Surgery and the Founding Director of the ImmunoTransplantation Center of the University of Pittsburgh Cancer Institute (2000-2017).
The research of Dr. Kalinski addresses: 1) Cell-based immunotherapies of cancer with focus on dendritic cell (DC) therapies; and 2) Therapeutic reprograming of tumor microenvironments (TME) to enhance local infiltration of immune cells and enhance the therapeutic effectiveness of immune checkpoint inhibitors (ICI) and other cancer treatments. Dr. Kalinski has authored over 150 scientific publications and developed multiple INDs and investigator-sponsored clinical trials in these areas (melanoma, brain, prostate, colon, ovarian and breast cancers). He has extensive experience building and leading Team Science programs and collaborative projects within P01s (melanoma, colon, ovarian), SPOREs (melanoma and ovarian) and R01s.
His work has been funded by multiple grants from the National Cancer Institute (NIH/NCI), Department of Defense Congressionally-Directed Medical Research Program (CDMRP), philanthropy, biotech and pharma partners. He has served on Boards of Directors and Editorial Boards of several professional organizations and scientific journals, and as a scientific consultant and reviewer for multiple grant-funding agencies and scientific journals in the United States and Europe.
Talk Title: Sensitizing Cold Tumors for the Therapeutic Efficacy of Immune Checkpoint Inhibitors
The presence of CD8+ cytotoxic T cells (CTLs) in tumor microenvironments (TME) is critically needed for the clinical effectiveness of PD-1 blockers and other therapies of solid tumors. In contrast, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are associated with poor outcomes.
We developed a combinatorial chemokine-modulating (CKM) strategy, involving TLR3 ligands, IFNa and COX2 blockers, which selectively induces CTL attractants (CXCL9, CXCL10 and CCL5), but suppress Treg attractants, such as CCL22, in the TMEs of multiple cancer types. Our alternative strategy is intratumoral (i.t.) injection of “type-1-polarized” dendritic cells (DCs) which selectively attract CTLs, NK and Th1 cells, but not Tregs.
Importantly for the feasibility of using systemic CKM infusions to activate multiple lesions of patients with disseminated tumors, CKM induces CTL attractants preferentially in tumor lesions, abrogating their intrinsic heterogeneity, but not in healthy tissues. Local or systemic CKM application or i.t. DC therapies are effective in promoting intratumoral accumulation of the spontaneously arising tumor-specific CTLs, showing strong therapeutic synergy with PD-1/PD-L1 blockade in several nominally-PD1-resistant mouse tumor models.
The antitumor effectiveness of the CKM/anti-PD-1 therapies is further enhanced by systemic vaccination with a specialized DC vaccine (aDC1s), which selectively enhances the expression of CXCR3 and CCR5 (receptors for CXCL9, CXCL10 and CCL5) on tumor-specific CTLs, facilitating their homing to the CKM-treated tumors.
Our ongoing clinical trials in advanced colon, breast, prostate and ovarian cancers evaluate the immunologic effectiveness of the CKM in functionally reprogramming the TME and its clinical activity, when combined with PD1 blockade and/or aDC1 vaccines.
Wayne W. Hancock, Ph.D.
Professor, Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
After MD/PhD degrees and pathology training, my career has involved academic positions in Australia and the US, plus several years in biotech. Throughout, I have been interested in the mechanisms of disease, and how these processes can be therapeutically regulated. E.g., the search for therapeutic strategies to enhance outcomes post-transplant led to studies of the anti-inflammatory properties of anticoagulant molecules, ways to improve the outcomes of xenotransplantation via induction of "protective" genes, back to allotransplantation and studies of novel costimulation molecules, and then the roles of chemokine and their receptors in alloresponses. For the past decade, my work has focused on biochemical, molecular and therapeutic studies of Foxp3+ T-regulatory (Treg) cell biology (with >80 papers to date in PubMed involving studies of murine and human Foxp3). I am a tenured Professor Pathology and Laboratory Medicine at the University of Pennsylvania and Chief of the Division of Transplant immunology at the Children’s Hospital of Philadelphia
Talk Title: Overcoming Treg Suppression to Promote Anti-Tumor Immunity
My current work is currently focused on the role of Foxp3+ T-regulatory (Treg) cells in immuno-oncology and transplantation and includes mechanistic and translational studies of the roles of HATs, HDACs and co-regulatory complexes through murine and clinical studies. With relevance to immune-oncology, the benefits of immunotherapy are often limited by an immunosuppressive environment at the tumor site involving Foxp3+ Tregs and myeloid-derived suppressive cells. We have developed self-delivering FANA antisense oligonucleotides (ASO) against human FOXP3 that were screened for their ability to knockdown FOXP3 and decrease human Treg suppressive function in vitro. Selected FANA were then tested in immunodeficient NSG mice reconstituted with human PBMC and shown to knockdown human FOXP3 in vivo. We also developed FANA ASO against murine Foxp3 that knocked-down Foxp3 mRNA and protein expression in vitro and in vivo, decreased Treg suppressive function and inhibited tumor growth in syngeneic lung tumor models. In summary, we have developed highly efficacious FANA ASO lead candidates that can knockdown FOXP3, inhibit Treg function and promote antitumor immunity and are proceeding with IND-enabling studies.
Fabiana Perna, Ph.D.
Associate Professor, Department of Medicine, Division of Hematology/Oncology, Indiana University
Fabiana Perna is a physician-scientist focused on the pathogenesis and treatment of hematological malignancies. She holds a full-time faculty position in tenure-track as an independent investigator in the Department of Hematology/Oncology of the Indiana University School of Medicine (IUSM). She completed clinical training as hematologist under the mentorship of Dr. Bruno Rotoli, leading hematologist in Italy. In 2008, she joined the laboratory of Dr. Stephen Nimer at Memorial Sloan Kettering Cancer Center, where she acquired scientific skills to model myeloid malignancies with cord blood CD34+cells. During that time, she contributed investigating the role of several recurring epigenetic mutations inhematopoiesis, while completing a PhD program. These studies were published on several high-impact scientific journals and, she was awarded an American Italian Cancer Foundation fellowship, the clinical fellowship of Memorial Sloan Kettering Cancer Center, the Translational Research Training in Hematology (TRTH) and a competitive American Society of Hematology (ASH) Scholar Award. At the end of 2012, she joined the laboratory of Dr. Michel Sadelain, at MSKCC, where she worked as a senior scientist. Given the exciting times in cancer immunotherapy and her previous expertise in myeloid malignancies, she developed a compelling platform, which integrates proteomics and transcriptomics to unbiasedly identify Chimeric Antigen Receptor (CAR) T cell targets for Acute Myeloid Leukemia (Perna Fet al., Cancer Cell 2017). She was awarded a Technology Development Fund from MSKCC of $500K and is co-inventor of four licensed patents on CAR T cells. In June 2019 she joined Indiana University School of Medicine as an independent investigator with her own lab and large start-up funds. Here, she received one grant of $100,000 from the Leukemia Research Foundation, three internal grants from IUSM and the IU Cancer Center ($116,000), one large award ($2M) from a pharma/biotech to develop novel CAR T-cell therapy. She has published three papers as senior and last author (37 peer-review publications in total) and is an active member of three ASH Scientific Committees. Here, she leads a project on emerging CAR T cells toxicities resulting in a series of manuscripts and an ASH workshop. Further, she obtained a permanent medical license from the Indiana Medical Board and ABIM board eligibility that allow her to see patients within the Bone Marrow Transplantation unit of the University Hospital and IU Simon and Bren NCI-Comprehensive Cancer Center Cancer Center. Dr. Perna lab’s research interests focus on developing novel methods for the identification of novel cell surface targets that could be suitable for immune-based therapeutic interventions. These studies also contribute to our understanding of the contribution of an altered surfaceome to cancer development and progression.
Talk Title: In Search of Novel Targets for Immune-based Therapeutic Interventions in Hematologic Malignancies
Targeting tumor antigens with immunotherapy is rapidly emerging as a promising approach for cancer treatment. The accumulation of genetic and epigenetic aberrations, the hallmark of malignancy, generates transcriptional and proteomic diversity, that also affects the cancer surfaceome, thus providing targets promoting the disease initiation and progression, and for use of immunotherapy.
Identifying biologically and therapeutically relevant surface targets is critical to ensure effective and safe cancer immunotherapies. However, our knowledge of the contribution of an altered surface proteome to cancer pathogenesis is still in development. Recent technological advances are now providing the necessary means to comprehensively map and analyze the cancer-specific surfaceome. These include high-quality Mass-Spectrometry methodologies and integrative bioinformatics tools. These are helping overcome the challenge of studying surface proteins that present with low abundance, high hydrophobicity and heavy post-translational modifications compared to intracellular proteins. Nevertheless, our ability to predict the therapeutic value of candidate molecules remains imperfect and it requires careful assessment of their abundance in cancer stem cells and dominant cancer clones, in large patient cohorts. As importantly, the safety of candidate molecules requires evaluation in normal tissues beyond normal counterparts. We will discuss one story from the lab focused on Multiple Myeloma (MM).
MM is an incurable malignancy of plasma cells. To identify immune-therapeutic targets for MM, we integrated Mass-Spectrometry and RNA-seq analyses from seven MM cell lines and 900+ MM patients. We identified the 326 surface proteins commonly and highly expressed and with functional relevance. We validated their expression in 30+ primary patient samples with relapsed/refractory MM, including patients who relapsed after BCMA Chimeric Antigen Receptor T-cell therapy and several normal tissues, including primary normal hematopoietic stem cells and T cells. By using a CRISPR/Cas9 system in MM cells, we first defined the biological consequences of genetically targeting top candidates and found that six top targets impact MM cell growth and migration as well as T-cell proliferation. Further, we found that knock-out (KO) of candidate targets sensitized MM cells to the killing effects of Venetoclax. Given that, we developed a bispecific T-cell engager targeting one of those targets and showed efficacy in killing MM cells. The target discovery platform we developed may thus support development of novel immune-based therapies for the treatment of patients with relapsed or refractory MM.
Dr. Sandro Matosevic, Ph.D.
Assistant Professor, Department of Industrial & Physical Pharmacy, Purdue University
Sandro Matosevic, Ph.D. is an assistant professor in the Department of Industrial and Physical Pharmacy at Purdue University. His lab studies immunotherapy of solid tumors using engineered natural killer cells, immunometabolic reprogramming and innate immunity.
Talk Title: Reprogramming of Natural Killer Cells as Immunotherapies for Solid Tumors
Lili Yang, Ph.D.
Associate Professor, Department of Microbiology, Immunology & Molecular Genetics, Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, University of California at Los Angeles
Talk Title: Allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy
Cell-based immunotherapy has become the new-generation cancer medicine, and “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. By combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.
Cassian Yee, M.D.
Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center
Dr. Yee is Professor in the Division of Cancer Medicine, Co-Director of the Adoptive Cellular Therapy Platform and Director of Solid Tumor Cell Therapy at UT MD Anderson Cancer Center. He received his medical training in Canada, residency at Stanford and fellowship at Fred Hutchinson Cancer Research Center. He is an elected member of the American Society of Clinical Investigators, CPRIT Clinical Investigator, co-Leader of the Stand Up to Cancer- AACR/CRI Dream Team and recipient of translational scientist awards from Burroughs Wellcome Fund, Damon Runyon Cancer Research Foundation, and the Rao Potul Basic Science Award. Over the last 20+ years, Dr. Yee has pioneered a form of ACT, known as Endogenous T Cell (ETC) therapy, using peripheral blood to generate a uniform population of antigen-specific memory T cells. He has conceived and executed > 20 IND-approved first-in-man clinical studies establishing principles of persistence, memory and antigen-spreading as fundamental to the success of adoptive cell therapy in a modality known as Endogenous T Cell (ETC) therapy, including the first-in-class use of tetramer-guided cell sorting to generate memory T cells and the first prospective trial using ETC in combination with immune checkpoint therapy. He is corresponding or lead author in > 80 publications, including The New England Journal of Medicine, Nature, Science, Science Immunology, Science Translational Medicine, Nature Medicine, Journal of Clinical Oncology, Journal of Experimental Medicine, Gastroenterology and Cancer Immunology Research. He holds > 15 worldwide inventions on ex vivo generation of antigen specific T cells, memory reprogramming, and antigen discovery and seeks to extend immunotherapy-based cancer treatments globally. His work converges multidisciplinary and collaborative approaches in bioengineering, metabolism, molecular immunology and cellular biology to develop effective immunotherapy strategies and adoptive cellular therapy, in particular, as a treatment modality for patients with malignant diseases.
Talk Title: Endogenous T Cell Therapy: The New Math in Adoptive Cell Therapy
Adoptive Cell Therapy (ACT) has enjoyed a revival in recent years with the approval of CAR T cells for the treatment of patients with B cell malignancies. Advancing the use of adoptively transferred T cells for the treatment of patients with solid tumor and other hematologic malignancies however, will require addressing numerous effector cell intrinsic as well as tumor micro environmental hurdles and exploiting a broader ACT platform that includes not only engineered CAR-T cells, but also other forms of ACT including Endogenous T Cell (ETC) Therapy Endogenous T cell (ETC) therapy requires specialized methods to isolate and expand from peripheral blood, tumor-reactive T cells, often present at very low frequency, and, by sourcing effectors from the entire TCR repertoire, provide the greatest flexibility in delivering a T cell product of defined specificity and phenotype. Several first-in-human studies performed by our lab demonstrate the importance of antigen spreading in generating long-lasting clinical responses as well as identifying T cells with specialized memory properties. The ETC therapy approach allows for the greatest flexibility in targeting personalized and shared tumor-associated antigens and rapid implementation of adoptive cell therapy from epitope identification to T cell infusion. To broaden the pool of patients and extend the use of adoptive cell therapy to several solid tumor malignancies such as ovarian, lung, GI and breast cancers, we have validated several high value target tumor antigens that are expressed in significant fraction of these tumors. The use of memory-type T cells targeting tumor-associated antigens, provides a unique opportunity to evaluate the combination of adoptive cellular therapy together with immunomodulators such as immune checkpoint inhibitors and costimulatory agonists in a strategy that addresses both intrinsic and extrinsic tumor microenvironmental challenges to successful immune-based therapy.
Dr. Yoon Yeo, Ph.D.
Professor of Industrial & Physical Pharmacy and Biomedical Engineering, and Associate Department Head, Purdue University, West Lafayette, IN
Dr. Yoon Yeo is a Professor and Associate Department Head of Industrial and Physical Pharmacy at the College of Pharmacy with a joint appointment in Biomedical Engineering and a Showalter Faculty Scholar at Purdue University. She received her B.S. in Pharmacy and M.S. in Microbial Chemistry at Seoul National University in Korea, and her Ph.D. in Pharmaceutics at Purdue University, West Lafayette, USA. She obtained post-doctoral training at the Massachusetts Institute of Technology and returned to Purdue to join the faculty in 2007. Her research focuses on nanoparticle surface engineering for drug delivery to solid tumors, intracellular delivery of peptide antibiotics, anion-resistant non viral gene vectors and functional biomaterials for immunomodulation.
Talk Title: Nanoparticle Engineering for Chemoimmunotherapy of Cancer
Immune checkpoint blockade aims to rekindle host immune responses against cancer by interfering with cellular interactions that suppress cytotoxic T-cell activities. However, a critical limitation of immune checkpoint blockade is that it currently benefits only a fraction of patients with tumors pre-infiltrated by T cells (“hot” tumors). “Cold” tumors, which lacks in adequate pre-existing T-cell immune responses, remain refractory to immune checkpoint inhibitors. In an effort to overcome this challenge, we develop nanoparticle formulations that can leverage the immune system. In one example, we exploit the adjuvanticity of drug carriers to stimulate antigen presenting cells. Alternatively, we deliver anti-cancer drugs in a sustained manner to generate tumor neoantigens in situ. I will present how drug carriers can help enhance cancer immunotherapy with these examples and what remains a challenge in future development of cancer chemoimmunotherapy.