Robert H. Vonderheide - US grants

The recent discovery of tumor-associated antigens (TAA) in certain human malignancies has prompted renewed efforts to develop antigen- specific immunotherapy of cancer. However, most TAA described thus far are expressed in one or a few tumor types, and among patients with these types of tumors, TAA expression is not universal. For this project, it was hypothesized that the telomerase catalytic subunit (hTERT) might function as a nearly universal tumor antigen. More than 85% of human cancers exhibit strong telomerase activity whereas normal adult tissues with few exceptions do not. In a human system, preliminary work has demonstrated that a peptide derived from hTERT is capable of triggering cytotoxic T lymphocytes (CTL) that lyse hTERT+ tumors in a MHC Class I-restricted fashion. Further investigation of hTERT as a widely expressed tumor antigen is the focus of this project. The proposed experimental approach is based on the hypothesis that epitopes recognized by cytotoxic T lymphocytes can be deduced from genes selectively expressed in tumors and subsequently tested by evaluating CTL reactivity against antigen-positive tumor cells. The ultimate goal is the identification of multiple hTERT epitopes that would be useful in the design of hTERT-directed immunotherapies. Specifically, the project aims to: (1) Identify multiple cytotoxic T lymphocyte epitopes derived from hTERT and restricted to the most common MHC Class I alleles, (2) Compare the generation of hTERT-specific CTL from the peripheral blood of cancer patients and the generation of such CTL from normal donors, and (3) Evaluate hTERT-specific CTL for cytotoxicity against primary tumors and normal cells that express telomerase. The applicant is an M.D. who will have completed his clinical fellowship training in hematology-oncology prior to the proposed starting date. The research will be performed in a laboratory at the Dana-Farber Cancer Institute under the sponsorship of Dr. Lee M. Nadler, a recognized leader in the field of tumor immunology with a strong track record for fostering the career development of physician-scientists.

DESCRIPTION (provided by applicant): Molecules essential for tumor growth and development represent promising targets for novel immunotherapy of cancer, yet host immunosuppressive factors impose major challenges for translating this hypothesis into clinical success. This proposal addresses these obstacles in breast cancer by combining a novel vaccine against the human telomerase reverse transcriptase (hTERT) and survivin in combination with anti-CD25 antibody daclizumab in patients with hormone receptor positive (HR+) metastatic disease. hTERT and survivin are expressed in >90% of human breast tumors but rarely in normal cells, and each critically contributes to the malignant phenotype. We have shown that cytotoxic T lymphocytes recognize peptides derived from hTERT and survivin and kill tumors cells expressing these proteins across a wide range of histologies. During the previous funding period, we vaccinated patients with metastatic breast cancer with a single hTERT peptide and demonstrated the induction of hTERT- specific CD8+ T cells in both blood and tumor, associated with major alterations in the tumor micro- environment and increased overall survival. We also found that immunosuppressive regulatory T cells (Tregs) are abundant in breast cancer and in a pilot clinical study, a single infusion of the anti-CD25 monoclonal antibody (mAb) daclizumab resulted in prolonged depletion of CD4+ Foxp3+ CD25+ Tregs in patients at a level not previously achievable. We hypothesize that a vaccine against hTERT and survivin in combination with daclizumab to deplete regulatory T cells can induce anti-tumor immune responses and offer clinical benefit for patients with HR+ metastatic breast cancer. To test this hypothesis, we propose two randomized clinical trials employing a second-generation vaccine already approved for investigation by FDA and involving multiple hTERT and survivin peptides in adjuvant, GM-CSF, and the CRM197-containing pneumococcal vaccine Prevnar (PCV), the latter a novel approach to induce T cell help. In Aim One, HLA-A2+ patients with HR+ metastatic breast cancer with progression through first or subsequent hormonal therapy for metastatic disease will be randomized to receive next appropriate hormonal therapy and hTERT/survivin/PCV vaccination with or without daclizumab to assess the effect of Treg depletion on the immunogenicity of the vaccine. In Aim Two, HLA-A2+ patients with HR+ metastatic disease and progression through first hormonal therapy for metastatic disease will receive second-line hormonal therapy with or without vaccine. The move from Aim One to Aim Two, therefore, represents a smooth and justified extension of our approach to a larger cohort of healthier and less heavily pretreated patients with HR+ metastatic disease. In both aims, immunological monitoring of T cell responses and Treg modulation will be performed to provide insights into immune mechanisms related to the observed clinical effects. The goal is to establish an immunologically potent vaccine that offers clinical benefit for patients with HR+ metastatic breast cancer. PUBLIC HEALTH RELEVANCE: We aim to determine the immunological and clinical impact of a novel vaccine targeting hTERT and survivin with and without daclizumab in patients with metastatic hormone receptor positive breast cancer. All patients in the proposed clinical trials will also receive the next appropriate hormone therapy per standard of care. The long-term goal is to develop an immune-based therapy that offers clinical benefit to patients with hormone receptor positive breast cancer.

DESCRIPTION (provided by applicant): T lymphocytes are prime mediators of tumor immune surveillance, particularly for patients with melanoma in whom T cell infiltration into tumors predicts clinical outcome and for whom immunotherapeutic strategies have in some cases shown clinical utility. Here, we propose to evaluate the clinical and immunological impact of simultaneously targeting CD40 and CTLA-4 in patients with melanoma. Both molecules are critical regulators of the cancer immune response that can be exploited therapeutically. CD40 is a cell-surface receptor that mediates activation of antigen presenting cells and plays an important role in establishing tumor immunity. CTLA-4 is a negative regulator of T cell activation, and blockade of the CD80/86-CTLA-4 pathway with CTLA-4 monoclonal antibody (mAb) enhances anti-tumor T cell responses and leads to tumor rejection. In mice, combination therapy with agonist CD40 mAb and blocking CTLA-4 mAb enhances the induction of tumor-specific T cells and tumor rejection without toxicity. It is the central hypothesis of this proposal that higher potency T cell activation and improved clinical activity can be achieved by combining CD40 activation with CTLA-4 blockade in patients with melanoma. To test this hypothesis, we propose to combine the agonist CD40 mAb CP-870,893 with the blocking CTLA-4 mAb tremelimumab in patients with metastatic melanoma. Although each fully human mAb has been tested separately and shown promise in patients with melanoma, the combination has not. Our approach represents a novel strategy to step on the gas while cutting the brakes. Moreover, the approach emanates from the fundamental oncological tenet that prioritizes combining two or more agents that have distinct mechanisms of action, non-overlapping clinical toxicities, and a definite single-agent response rate. Preclinical toxicology studies demonstrate an acceptable safety profile of combined CP-870,893/tremelimumab therapy in non-human primates. Our investigator-sponsored phase I study of CP-870,893 and tremelimumab has received full regulatory approval and is open to enrollment (NCT01103635). Three patients have begun treatment without major toxicity indicating feasibility. If funded, we will (1) Establish the maximum tolerated doses of CP-870,893 given every 3 weeks in combination with tremelimumab given every 12 weeks in patients with metastatic melanoma, and (2) Determine the immunological mechanism of CP- 870,893/tremelimumab in patients by assessing treatment-related activation and function of antigen presenting cells, modulation of T cell subsets, and induction of tumor antigen-specific T cell using a panel of state-of-the-art immune assessment assays.

DESCRIPTION (provided by applicant): It is widely accepted that the immune system can exert either positive or negative influences on tumor growth. In many instances, tumors create an immunosuppressive microenvironment which contributes to tumor escape from immune destruction, particularly in pancreatic ductal adenocarcinoma (PDA). We have previously demonstrated that CD40 agonists can alter the tumor microenvironment and trigger a macrophage-dependent destruction of PDA in both humans and genetically engineered mice. Moreover, using a novel genetic lineage-tracing methodology, we now have preliminary data that invasive behavior and other elements of the metastatic cascade occur at the earliest stages of disease and are critically regulated by inflammation. Thus, we hypothesize that targeting immunosuppressive mechanisms in PDA will provide novel approaches to therapy for this otherwise treatment-resistant disease. In particular, we hypothesize that CD40 activation can re-educate both macrophages and T cells to trigger regression of a primary PDA tumor and impede metastatic spread in concert with other elements of the immune system. Our ultimate goal is to devise new therapies for PDA based on an understanding of immune regulatory networks in the tumor microenvironment. This proposal uses the multi-PI mechanism and will incorporate both mouse models and human patients. Specific Aims are to: (1) Understand the immunological mechanism(s) underlying the anti-tumor effect of agonist CD40 mAb, (2) Understand how inflammation and CD40 activation influence the metastatic cascade, 3) Determine the clinical and immunological impact of CD40 mAb in a clinical trial of patients with resectable pancreatic carcinoma.

Project Summary The Immunobiology Program aims to: 1) Understand the fundamental aspects of immune biology, including activation, differentiation, inactivation, and transformation as these relate to cancer; 2) Forge a comprehensive understanding of tumor immune surveillance using state-of-the art in vitro, animal model, and human experimental systems; and 3) Translate novel clinical strategies for immunotherapy of cancer by the design, implementation, and analysis of proof-of-concept human clinical trials. Established in 1974, this Research Program received ?Outstanding? merit at the time of the last CCSG renewal application. The Program is Co- Led by Robert Vonderheide, MD, DPhil, an expert in tumor immunology and immunotherapy, and Warren Pear, MD, PhD, an expert in the molecular biology of leukocyte development and malignant transformation. Drs. Vonderheide and Pear are experienced, NCI-funded investigators who are highly collaborative and whose research interests span the realm of basic and translational science. There are 34 Program members from 10 departments and four schools with long-standing intra- and inter-Programmatic collaborations spanning the Basic as well as Clinical Programs. Through these interactions, the members' collective expertise serves as a rich resource for the pursuit of interdisciplinary approaches to fundamental questions about the immunobiology and immunotherapy of cancer. Members include national leaders in basic immunology, tumor immunobiology and translational immunotherapy. The Program Co-Leaders facilitate interactions through multiple weekly seminars and meetings, promotion of collaborative grants and projects, an annual research retreat, Pilot Project grants, and training programs. During the current project period, Program Leaders recruited new members, expanded important forums, facilitated new collaborative grants, initiated new ACC-wide initiatives, and were actively involved in decisions regarding new and existing Shared Resources. Currently, Program members have $20.6M in research grant funding (annual direct costs), of which $11.3M is peer-reviewed and $2.2M is NCI-funded. During the current project period, Program members published 421 cancer-related publications, many of which are in top journals in the field. Of these, 17% are intra-Programmatic, 24% are inter-Programmatic, and 29% are multi-institutional.

SUMMARY The Administrative Core A of this Program Project is designed to provide scientific leadership, effective communication and an administrative support structure to ensure the coordination of all Program Project activities. In 2015, the four PIs of this multiple PI P01 proposal reported in Nature that hypofractionated radiation and dual checkpoint blockade activated anti-tumor T cell immunity in both mice and patients via non-redundant mechanisms, explaining the apparent synergy. This newly proposed Program Project seeks to deeply extend our knowledge regarding the intersection of radiation and immunotherapy of cancer. The proposed program has three projects and three cores, with a balance of senior leaders in multiple disciplines working alongside more junior faculty investigators as a team. We have taken advantage of the large and efficient administrative staff and the centralized research organizations at the Abramson Cancer Center (ACC) of the University of Pennsylvania to achieve our objectives. Strong institutional commitment from the ACC and Penn has helped lay the foundation for our scientific and translational achievements. The essential services provided by the Core A include: administrative support for all of the investigators in each project and core; fiscal management and oversight for all components of the Program Project; and organization and communication of all Program Project meetings and activities. The overall goal of this Core is effective and efficient leadership of the P01. The roles of the Core Director, Co-Director and administrative staff are to facilitate communication while stimulating scientific and technological interactions. In order to achieve this goal, the Core has established three objectives: (1) Establish and maintain an administrative structure to provide support for and management of all Program Project activities, (2) Foster an environment to maximize collaborative research among Program Project investigators and between other P01 and NCI initiatives, and (3) Ensure compliance with all institutional, governmental and NCI regulations and policies.

The goal of the Abramson Cancer Center (ACC) of the University of Pennsylvania is to bring together more than 310 members to transform the paradigm of patient-centered cancer care and cancer control by integrating high impact Programs of basic, clinical, and population-based research, fostering pioneering scientific discoveries, and facilitating the translation of these discoveries into clinical practice. In doing so, the ACC builds upon the great clinical cancer care at renowned hospitals of the University of Pennsylvania and the Children?s Hospital of the Philadelphia. The ACC continues to build on its significant historical strengths in basic cancer biology, translational immunotherapy, and population science research. By leveraging the infusion of new Institutional resources and significant philanthropic resources, the ACC will continue to innovate to reduce the burden of cancer in our catchment area during the next project period and will seek to: (1) Accelerate and expand its leadership in adoptive cellular immunotherapy, combination immune checkpoint therapies, and vaccine development for both prevention and treatment of cancers. (2) Increase translation of cancer basic biology through the philanthropic and Institutionally supported ACC Translational Centers of Excellence that integrate basic, translational and clinical scientists from the ACC Programs to impact on the prevention, detection, and treatment of specific types of cancers that afflict our catchment area. (3) Accelerate precision cancer medicine through novel Molecular Imaging, the Center for Personalized Diagnostics, the Molecular Tumor Board, and the Circulating Tumor Material Developing Core, which were implemented in the past project period, and the implementation of the Center for Rare Cancers and Personalized Therapy in the next project period. (4) Innovate means to understand, prevent, and treat therapy-resistant cancers by incorporating genomics, epigenomics, informatics and research in cancer metabolism, which is frequently re-wired in resistance to targeted therapies. (5) Lead population-based research through recruitment and research tools in genetics and complex traits with an emphasis on cancer epidemiology. Implement projects in cancer molecular epidemiology among patients of African descent and accelerate our Outreach Program to increase research relevant to our catchment area. (6) Launch a new Brain and Behavior Change initiative and harness new tools from cognitive neurosciences to control cancer by modulating behaviors that predispose to smoking or contribute to obesity. Lead in Toxicology and Environmental Carcinogenesis to understand environmental toxins and impact the health of patients with mesothelioma in our catchment area.

Abramson Cancer Center at the University of Pennsylvania; Animals; Bioinformatics; Biostatistics Core; Ensure; Environment; Fostering; Government; Immune; Immune checkpoint blockade; Immunotherapy; Institutionalization; Maligt Neoplasms; meetings; Policies; Principal Investigator; programs; Radiation; Regulation; Research; Research Personnel; Structure;

Project Summary Immunotherapy has revolutionized the treatment of a variety of advanced cancers, especially immune checkpoint blockade (ICB). Although newly FDA approved antibodies that block CTLA-4 or PD-1 offer hope for some patients, not all patients respond, and others relapse after initial response. Consequently, there is a great importance in evaluating immune checkpoint blockade with other therapies that trigger immune activation. Based on extensive preclinical and clinical results from our group, we are focused on the combination of immune checkpoint blockade with hypofractionated radiotherapy (HFRT). The rationale for this approach is emerging evidence from our group and others that irradiation of tumors can stimulate the immune system, perhaps by releasing tumor-associated antigens which may allow for better response to the immunomodulatory agents. In a previous phase I trial of ipilimumab with HFRT in patients with advanced melanoma, we observed some cases of deep objective responses, reminiscent of prior case reports, but only in 18% of patients. In extensive preclinical experiments in which we modeled the interactions of radiation and ICB, we found across multiple histologies (breast and pancreatic cancer, melanoma) that blockade of CTLA-4 and PDL-1/PD- 1 in combination with HFRT achieved major tumor regressions and complete responses in mice without major toxicity (Tyman-Saint Victor, Nature, 2015). Both CTLA-4 and PD-L1 blockade are required for optimal therapy as each modality non-redundantly improves response and immunity. PD-L1 blockade is especially important to overcome immune resistance, as our data show that efficacy of HFRT plus CTLA-4 blockade alone is limited by PD-L1 expression in the tumor, a finding validated in samples from our initial trial. Based on these pre-clinical data, we propose two immediate clinical trials in collaboration with Core C combining agents that block CTLA-4 (ipilimumab or tremelimumab) or PD- 1/PD-L1 (nivolumab or durvalumab) with HFRT: (Aim 1) a phase 2 randomized trial of ipilimumab and nivolumab with or without HFRT in patients with metastatic melanoma, and (Aim 2) a phase 1 trial of tremelimumab and durvalumab in patients with metastatic pancreatic, lung, and breast cancer. In Aim 3, we will apply a comprehensive plan for immune assessment with collaborations across all Projects and Cores in this P01 to determine the immunological mechanisms of our approach. The expected clinical and immunological findings will significantly advance the development radiation and immune checkpoint therapy for patients. 1

The long-term goal of this P01 is to understand the intersection of radiation biology and cancer immunology and to translate this research into better therapies with curative potential for patients with cancer. Radiation therapy (RT) can systemically impact the immune system, and recent clinical success of PD1 and CTLA4 immune checkpoint blockade (ICB) has given rise to our overarching hypothesis that the immune stimulatory effects of RT can expand the spectrum of clinical responsiveness when combined with dual ICB across multiple histologies. Our preliminary data and investigative approach bridges studies in both patients and animal models. To achieve our goals, we have developed three Projects, which require close coordination of projects and cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) nivolumab (PD1 mAb) and ipilimumab (CTLA4 mAb) with or without hypofractionated RT (HFRT) in a randomized phase II study in metastatic melanoma; and (ii) and tremelimumab (CTLA4 mAb) and durvalumab (PDL1 mAb) with HFRT at two dose schedules in metastatic pancreatic, lung, and breast carcinoma. In Project 2, we will determine the role of RT in establishing cancer immunity, evaluating the mechanism of anti-viral signaling through pattern recognition receptors and non-coding RNA and examining dendritic cell biology and CD40 activation. In Project 3, we will define the genetic and epigenetic basis of resistance to RT and ICB and examine PDL1 independent pathways to overcome this. Biomarkers revealed in Projects 2 and 3 will be examined using human samples from the clinical trials in Project 1. The Cores for this P01 are essential for our progress including provision of administration support for collaboration (Core A), a state-of-the-art platform for small animal radiation (Core B), and bioinformatics and biostatistical approaches to drive deep learning from data generated in all Projects (Core C). The potential for paradigm shifting impact is to transform the indication of RT from ?local therapy? to key part of a novel ?systemic? immune therapy for meaningful efficacy against metastatic and advanced cancer.

Project Summary During the current project period, the Abramson Cancer Center (ACC) used Developmental Funds to support innovative new research through a Pilot Project Program, and also to provide support to our Shared Resources. These funds have stimulated research in areas of strategic importance to the ACC. This support is essential to the ACC's ability to execute its responsibilities in stimulating transdisciplinary and translational research and to encourage research in areas of priority to both the ACC and the NCI. Pilot awards are issued based on a long-standing, well-established peer review process involving senior and junior ACC members from multiple departments and disciplines. This process is similar to the peer review process used by the NCI. During the current project period plus the last year of the previous project period, 32 pilot projects were awarded. 17 new externally funded grants were awarded to recipients ($2.3M annual direct costs) and another eight are pending. 33 peer-reviewed articles were published by recipients. Developmental Funds for Shared Resources were also used to support a developing animal pathology core, which is now a fully established Shared Resource in this renewal application. In the coming cycle, we are requesting Developmental Funds to continue our robust Pilot Project Program, to aid in the development of new Shared Resources, to provide support to our Staff Investigators and to continue our recruitment of faculty-level scientists in areas of strategic need.

Project Summary The Administrative Core is comprised of Cancer Center Administration and Senior Leadership. Abramson Cancer Center (ACC) Administration provides centralized coordination of resources and services required to facilitate the ACC's scientific mission to reduce the burden of cancer. Coordinated activities include: participation in the governance and decision-making processes of the Center; representation of the Center within the parent Institution; and the oversight and management of multiple CCSG-related activities. CCSG- relevant activities include: support of Planning and Evaluation; oversight of Shared Resources; support of faculty recruitment; management of the membership process and data, such as publications and grants; management of the Pilot Projects Program; space management; coordination and documentation of Center meetings; budgeting and financial management; and management of the CCSG application. ACC Administration is comprised of a cohesive group of highly experienced staff with the demonstrated expertise needed to enable the ACC to realize its mission and respond to the growing research needs of the membership. These key administrative staff members have clearly defined roles, responsibilities and reporting lines, ensuring that the administrative activities of the ACC are delivered in an effective and efficient manner. ACC Administration provides vital support to the ACC Director, Senior Leadership, Program Leaders, Advisory Groups, Shared Resources and members. Senior Leadership is a carefully selected group of nationally prominent individuals who have clearly defined roles while sharing overall responsibility for realizing the mission of the ACC, developing and implementing strategies that respond to the needs of members, and fostering a creative, cohesive cancer research environment that encourages transdisciplinary team science across the translational pipeline. Leaders identify scientific issues and strategic priorities and review progress toward achieving goals. Dr. Chi Dang has served as Director since 2011, replacing Dr. Craig Thompson. Dr. Caryn Lerman has continued in her role as Deputy Director, as have Dr. Lewis Chodosh as AD for Basic Research, Dr. Garrett Brodeur as AD for Pediatric Research, Dr. Timothy Rebbeck as AD for Population Science, and Dr. James Alwine as AD for Shared Resources. Dr. Roger Cohen replaced Dr. Lynn Schuchter as AD for Clinical Research. Three new AD positions were created: Dr. Robert Vonderheide was appointed AD for Translational Research, Dr. Carmen Guerra was appointed AD for Diversity and Outreach, and Dr. Brian Keith was appointed AD for Education and Training. Mr. Robert Wynne was promoted from AD for Finance to AD for Administration.

PROJECT SUMMARY Inter-tumoral heterogeneity ? the fact that every tumor has distinct genetic, epigenetic, and stromal features ? poses a challenge for precision cancer therapy. While genetic variants that influence a tumor?s response to targeted therapy (i.e. ?actionable mutations?) have received great attention, comparatively less is known about the causes of variation in the tumor microenvironment (TME). Nevertheless, such variation in the TME is likely to be of critical importance, as prior work has shown that the response to immunotherapy correlates with the abundance of T cells and other immune populations within a tumor [1,2]. We and others have shown, in the context of pancreatic ductal adenocarcinoma (PDA), that tumor-derived factors shape the microenvironment in vivo, dictating the relative abundance of different stromal populations. For example, tumor-derived GM-CSF recruits myeloid cells to the tumor, fostering an immunosuppressive environment [3,4], while tumor-derived Sonic Hedgehog causes an accumulation of myofibroblasts and other changes in the TME [5,6]. However, additional cancer cell-derived factors that act in similar fashion remain to be identified, representing an unexploited source of novel targets. In our preliminary work, we found that human PDA exhibits a wide spectrum of immune activity. Surprisingly, and in contrast to other tumor types, the presence or absence of an active immune signature was unrelated to the neo-antigen burden of a given tumor. We therefore hypothesize that cancer cell-intrinsic factors critically shape the immune microenvironment and drive immune heterogeneity. We further hypothesize that (i) a tumor?s immune makeup determines its response to immunotherapy and (ii) anti-tumor responses can be improved by modulating the immune infiltrate. Here, we propose an innovative approach to delineate the biology of immune heterogeneity in PDA, including novel implantable and genetically engineered mouse models studied in parallel with samples from an extensive tumor bank and prospectively collected from two clinical immunotherapy trials. Cellular, molecular, and clinical consequences of inter-tumoral heterogeneity will be assessed in the context of response to immunotherapy. Our ultimate goal is to understand and manipulate the immune microenvironment in PDA for therapeutic benefit, and we will approach this goal through the following three interrelated Specific Aims: Aim 1. Identify the molecular mechanism(s) underlying heterogeneity of immune infiltration Aim 2. Assess the impact of immune heterogeneity on the response to immunotherapy Aim 3. Elucidate the causes and consequences of immune heterogeneity in human PDA

Project Summary The Abramson Cancer Center (ACC) has a well-established internal, Institutional, and external Planning and Evaluation (P&E) process that engages leaders, members, and advisors from multiple disciplines, perspectives and levels. The goal of this process is to guide future directions, set priorities and prioritize investments of the Center while, at the same time, providing ongoing mechanisms to monitor, assess and adjust research progress, Programs, Shared Resources, allocations, and strategies. This cohesive process is supported by highly integrated and effective bodies, such as the Senior Leaders, Executive Committee, Program Leaders, Shared Resource Advisory Committees, and the External Scientific Advisory Board (ESAB), which provides critical advice and feedback from experts. The Planning and Evaluation process has resulted in changes in Program focus, development of new Cores, changes in clinical research operations, and prioritization of Developmental Funds. Complementing these efforts are Programmatic, Divisional and Center-wide research seminars, meetings and retreats that foster new interactions and collaborations with Penn colleagues and external experts. Strategic planning is embedded in the ACC and Penn culture. The ACC plan of 2008-2013 set forth the goals for this period, including accelerating the translation of basic science discoveries into investigator-initiated clinical trials, establishing a comprehensive molecular profiling and personalized medicine initiative, enhancing behavioral interventions to reduce cancer risk, and promoting translation of ACC research. Soon after his appointment, the Center Director, Dr. Dang, defined his vision through 2020, and charged a group to recommend strategies to realize the Center's goals in translational research and precision medicine. A defining accomplishment has been $20M from the Institution to establish innovative transdisciplinary programmatic efforts in translational cancer research, which are fueled by multi-year Institutional grants and resources in high priority areas. Rigorous internal review of Programs, Shared Resources, Developmental Funds, and strategic plan reviews by the ESAB ensure that the ACC continues to strive for excellence and adheres to NCI guidelines. The ACC responds to all ESAB recommendations and then reports on its actions. Taken together, the integrated P&E processes have successfully guided the growth and development of the ACC during the project period.

PROJECT SUMMARY ? Developmental Funds During the current project period, the Abramson Cancer Center (ACC) used Developmental Funds to support innovative new research through a robust Pilot Project Program, to support our Staff Investigators, to support our Developing Shared Resources, and to support new and talented faculty recruits. These funds stimulated research in areas of strategic importance to the ACC. This support is essential to the ACC's ability to execute its responsibilities in stimulating transdisciplinary and translational research and to encourage research in areas of priority to both the ACC and the NCI. Pilot awards are issued based on a long-standing, well- established peer-review process involving senior and junior ACC members from multiple Programs, departments, and disciplines. This process is similar to the peer-review process used by the NCI. During the current project period plus the last two years of the previous project period, 34 pilot projects were awarded. Fifteen new externally funded grants were awarded to pilot recipients (totaling $14.3M in direct costs) and another three external grants are pending review. Additionally, this work was disseminated to peers through 31 manuscripts in high-impact journals including Nature, Nature Medicine, JAMA, Cancer Discovery, and J Clin Onc. Other noteworthy outcomes from our pilots include performance of nine interventional clinical trials and launching of a Translational Center of Excellence in Cardio-Oncology and the Population Science Center of Excellence in lung cancer screening. Developmental Funds during the current cycle supported three Staff Investigators and two Developing Shared Resources (one in Circulating Tumor Material and one in Cancer Metabolism). Both Developing Shared Resources supported multiple high-impact publications (including papers in Nature, Cell, JCI, and PNAS), and services are now incorporated into full Shared Resources in this renewal application. Finally, Developmental Funds were used to aid in the recruitment of three talented faculty members (Dr. Kathrin Bernt, Pediatric Oncology; Dr. Kara Maxwell, Cancer Control; and Dr. Robert Maki, who arrived at Penn in 2020). In the coming cycle, we are requesting Developmental Funds to continue our Pilot Project Program, to provide support for two Staff Investigators, and to continue our recruitment of faculty-level scientists in areas of strategic need.

PROJECT SUMMARY ? Leadership, Planning and Evaluation Senior Leadership of the Abramson Cancer Center (ACC) is a carefully selected group of nationally prominent individuals who have clearly defined roles, and together share overall responsibility for realizing the mission of the ACC. Senior Leaders develop and implement strategies that respond to the needs of members, fostering a creative, cohesive, and comprehensive cancer research environment that encourages transdisciplinary team science across the translational pipeline for which the ACC is well-known. Senior Leaders foster and advance basic discovery in line with strategic priorities, facilitating clinical translation. The ACC has a well-established internal, Institutional, and external Planning and Evaluation (P&E) process that engages leaders, members, and scientific and community advisors from multiple disciplines and perspectives. The goal of this process is to guide future directions, set priorities, and prioritize investments of the ACC while at the same time, providing ongoing mechanisms to monitor, assess, and adjust research progress, Programs, Shared Resources, allocations, and strategies. This cohesive process is supported by highly integrated and effective bodies, such as the Director's Advisory Council, Executive Committee, Program Leaders Committee, and committees for Shared Resources, Community Outreach and Engagement, Cancer Research Training and Education, Pilot Funds, and Clinical Informatics. External Scientific Advisory (ESAB) and Community Advisory Boards (CAB) provide critical advice and feedback. The P&E process resulted in changes in Program infrastructure; development of new Shared Resources; new leaders, resources, and tools for COE; improvements in clinical research operations; strategic recruitments; and prioritization of Developmental Funds. Complementing these efforts are Programmatic and Center-wide research seminars, meetings, and retreats that foster new interactions and collaborations with Penn colleagues and external experts. A Strategic Plan in 2016 set forth the goals for this period, and upon appointment of Dr. Vonderheide as Director, the ACC conducted a Strategic Plan Update in 2018-2019. Seven priority areas were evaluated: Experimental Therapeutics, Biomedical Informatics, Population Sciences, Immune Health, Precision Oncology, Shared Resources, and Education and Training. Priority values include relevance to the catchment area, team science, translation of discovery, risk assessment, precision profiling, leveraging of big data, behavioral research, and education and training. Rigorous internal review of Programs, Shared Resources, Developmental Funds, and the strategic plan by Senior Leaders and the ESAB ensure that the ACC continues to achieve its highest aspirations and adheres to NCI guidelines. The ACC responds to all ESAB recommendations and then reports on its actions. Taken together, integrated P&E processes successfully guided marked growth and impact of the ACC during the current funding period.

Project Summary for ?Prioritizing Clinical Trials at NCI Cancer Centers Before, During, and After the COVID-19 Pandemic: A Descriptive and Ethical Analysis? In contrast to other clinical areas, National Cancer Institute (NCI) Cancer Centers are required to prioritize trials at the site level. However, Cancer Centers currently lack ethics guidance for how best to make prioritization decisions. These decisions have traditionally been viewed as a matter of scientific peer review, rather than as ethical judgments, and they have not been empirically studied. This is concerning given that allocation of shared, limited institutional resources for research ? from eligible participants and available research staff to lab space and beds ? has critical implications for who stands to benefit from research participation and scientific progress. Without studying how Cancer Centers prioritize trials, it is not possible to identify areas of variation, ethical challenges and concerns, or the strengths and weaknesses of different approaches. The pandemic offers a compelling opportunity to examine Cancer Center trial prioritization, as COVID-19 demanded restrictions on in-person research activities and reduced cancer trial enrollments, even as many new protocols were proposed, intensifying prioritization pressures. Overall, bioethics as a field has paid insufficient attention to trial prioritization, especially by sites, and there is no widely-accepted ethics framework to guide this task. There is, however, emerging discussion of trial prioritization developing in the literature ? and the pandemic has accelerated this progress, as sites struggled to prioritize an influx of COVID-19 trials. A group of bioethicists, including the study lead on this proposal, developed a novel framework for consolidating and prioritizing COVID-19 trials, with the potential for broader applicability to other disease areas. The objective of the proposed research is to build on this framework and other resources to produce a new ethics model for Cancer Center trial prioritization, using empirical bioethics and implementation science methods. First, we will use in-depth interviews with Cancer Center Associate Directors of Clinical Research and other knowledgeable informants to examine how Cancer Centers (selected on the basis of their size, type, and region to maximize diversity of perspective) have prioritized trials before and during the pandemic. In particular, interviews will probe ethical and implementation challenges, perceived successes and failures, desired guidance, and lessons and plans for the future (Aim 1). Next, we will compare these descriptive findings against the proposed ethics framework for prioritizing COVID-19 trials, identifying shortcomings, gaps, and areas for revision and adaptation for the specific context of cancer (Aim 2). Finally, we will combine these descriptive and normative analyses to develop a novel framework for ethical trial prioritization by Cancer Centers, with a focus on feasibility of implementation (Aim 3). Together, these aims will build the bioethics evidence base to inform Cancer Center trial prioritization policy, as well as whether and how NCI should guide these decisions, while contributing to bioethics capacity building by facilitating ethical trial prioritization by responsible decision-makers.