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Last Updated: 12/14/18

Beckman Research Institute/City of Hope Lymphoma SPORE

Principal Investigator Contact Information

Stephen J. Forman, M.D.
Professor and Chair
Department of Hematology & Hematopoietic Cell Transplantation
City of Hope
1500 East Duarte Road
Duarte, CA 91010
Phone: 626-256-4673

Larry W. Kwak, M.D., Ph.D
Vice President and Deputy Director, Comprehensive Cancer Center
City of Hope
1500 East Duarte Road
Duarte, CA 91010
Phone: 626-256-4673

Overview

The overall goal of the City of Hope Lymphoma SPORE is to develop novel therapeutics and prognostics representing the forefront of knowledge gained from observations in molecular biology and cellular immunology at City of Hope. Six clinical trials are proposed in this grant, five of which utilize agents (cellular products, small molecules, radiolabeled antibodies) that will be produced at City of Hope in our GMP Manufacturing Core and have been developed from our preclinical laboratory studies.

Project 1: CMV/CD19 bi-Specific CAR T cells combined with CMV vaccine as post-transplantation immunotherapy for non-Hodgkin lymphoma

Stephen J. Forman & Ryotaro Nakamura (Clinical) / Donald Diamond & Xiuli Wang (Scientific)

We propose selecting cytomegalovirus (CMV) pp65-specific T cells for ex vivo modification with our phase-I–tested CD19 CAR, infusing the CMV-CD19 bi-specific T cells into patients (in post-transplant and active disease settings), and then conducting an in vivo expansion via CMV-specific modified vaccinia Ankara (MVA) Triplex vaccine injections. This strategy is feasible since more than 70% of adults are CMV immune, the frequency of pp65-specific T cells in CMV+ donors is high, and there is clinical experience with adoptive cellular immunotherapy targeting the CMVpp65 antigen. Importantly, in the post-allo HCT setting, use of CMV selection has a low risk of inducing GVHD and the possible benefit of preventing CMV infection. City of Hope researchers have also developed a novel CMV vaccine, Triplex, which can safely stimulate CMV-specific T cell immunity, through endogenous T cell receptors (TCR)1. This vaccine will be administered to patients after infusion of CMV-CD19CAR T cells to provide an antigen boost as a means to in vivo expand the CMV-specific CAR T cells. Triplex is a multi-antigen recombinant MVA virus vaccine that has thus far proven safe and immunogenic in a phase I trial in healthy volunteers of either +/- CMV serostatus. It is currently under study in a phase II vaccine trial in allo HCT recipients (NCT02506933).

Hypothesis: CD19CAR-engineered CMVpp65-specific T cells will be capable of a) safely mediating antitumor activity in the auto and allo HCT settings; b) persisting following adoptive transfer; c) expanding in response to viral antigen in vivo (either vaccine-mediated or CMV-native); and d) sustaining the antitumor immune response long-term.These studies are significant in that they address poor post-HCT outcomes for patients with B cell NHL. Our approach is highly innovative in combining CAR T cells with CMV vaccine.

Specific Aim 1: Test bi-specific CMV-CD19CAR T cells manufactured to clinical scale as part of pre-IND studies.

Specific Aim 2: Pilot/feasibility studies of bi-specific autologous CMV-CD19CAR T cells +/- CMV vaccine following lymphodepletion or autologous HCT for intermediate grade CD19-positive NHL.

Specific Aim 3: Pilot/feasibility studies of donor-derived CMV/CD19 bi-specific T cells +/- CMV vaccine following allogeneic transplantation for intermediate grade CD19-positive NHL.

Project 2: Therapy-related leukemia following autologous transplantation for lymphoma

Ravi Bhatia (Scientific) / Smita Bhatia (Clinical)

Therapy-related myelodysplasia/acute myeloid leukemia (t-MDS/AML) is a lethal complication of autologous hematopoietic cell transplantation (aHCT) lymphoma. t-MDS/AML is characterized by poor response to conventional chemotherapy, and median survival of <10 months and is the leading cause of non-relapse mortality among aHCT recipients for HL/NHL. It is generally believed that hematopoietic stem cells (HSCs) exposed to cytotoxic therapy suffer genomic damage leading to malignant transformation. However, high inter-individual variation in t-MDS/AML risk suggests a potential role for genetic susceptibility. Previous reports (using a candidate gene approach) suggest an association between germline single nucleotide polymorphisms (SNPs) and t-MDS/AML risk. We are conducting a genome-wide association study (GWAS: Illumina® HumanOmni5-Quad BeadChip platform; 303 cases; 606 controls) to identify germline variants associated with t-MDS/AML; top SNPs will contribute to creation of genetic profile. Somatic mutations in leukemia-associated genes DNMT3A, ASXL1, and TET2 seen in peripheral blood in ~10% of older healthy population, are associated with >10-fold increase in risk for subsequent leukemia; targeted next-generation sequencing will be used to identify driver mutations. We observed altered gene expression in PBSC samples from patients who subsequently developed t-MDS/AML when compared with patients who did not. This information was used to develop a 38-gene PBSC classifier in an independent test set; this classifier will also contribute to the genomic profile. The elevated risk of t-MDS/AML after aHCT, coupled with the poor prognosis, present an unmet need for pre-aHCT identification of patients at increased risk for post-aHCT t-MDS/AML to guide use of alternative therapeutic options for HL/NHL management. We hypothesize that a combined clinical and genetic risk prediction model applied prior to aHCT will allow identification of HL/NHL patients at increased risk for post-aHCT t-MDS/AML. The City of Hope cohort with the available PBSC products will serve as the Discovery cohort (n=1,915). aHCT recipients for HL/NHL with PBSC product at the University of Nebraska or University of Minnesota will be utilized as an independent Validation cohort (n=2,036).

Specific Aim 1: To use the Discovery Cohort (COH), to develop a prediction model that includes clinical profile, as well as genetic profile, to optimize identification of patients at high risk for developing t-MDS/AML.

Specific Aim 2: To use an independent Validation Cohort (UMN+UNE), to test the validity of the optimized prediction model (Aim 1).

Project 3: Targeted immunotherapy for relapsed/refractory Hodgkin lymphoma

Eileen Smith and Robert Chen (Clinical) /David Colcher and Alex Herrera (Scientific)

For patients with relapsed/refractory classical Hodgkin lymphoma (HL) after induction treatment, standard of care is 2nd-line combination chemotherapy followed by autologous hematopoietic cell transplantation (AHCT). Complete response (CR) at the time of AHCT is the strongest indicator of post-AHCT prognosis1; thus, we have designed a clinical trial investigating enhanced 2nd-line therapy to increase the proportion of patients in CR at the time of AHCT. The PD-1 inhibitor nivolumab (NIVO) has recently been approved for use in HL patients relapsing post-AHCT. In Specific Aim 1 we propose a multicenter phase II study evaluating NIVO followed by response-adapted addition of standard ifosfamide, carboplatin, etoposide (ICE) chemotherapy as a bridge to AHCT. This regimen, NICE, is designed to maximize CR rates pre-AHCT. In Specific Aim 2 we augment the AHCT conditioning regimen with targeted radioimmunotherapy (RIT) to improve AHCT outcomes. This single-center phase II study combines standard BEAM (BCNU, etoposide, Ara-C, melphalan) chemotherapy with an Yttrium-90 (90Y)-labeled anti-CD25 antibody, basiliximab. Basiliximab directly targets radiation to CD25+ Reed Sternberg (RS) cells, as well as activated T cells and regulatory T cells (Tregs) throughout the HL tumor microenvironment (TME). The crossfire effect of 90Y kills nearby cells including CD25-negative RS and immune cells in the tumor. The two studies are complementary, with NICE participants eligible for enrollment to the aTac-BEAM trial. The overarching goal of this project is to improve overall outcomes for patients with relapsed/refractory HL, via separate clinical trials to improve pre-AHCT CR rates and post-AHCT survival. Gene expression and tumor spatial analysis studies will help to elucidate the role of the TME in responses to anti-PD-1-based therapy.

Specific Aim 1: Response-adapted second-line therapy for Hodgkin lymphoma using anti-PD-1 antibody nivolumab ± ICE as a bridge to AHCT (NICE trial).

Specific Aim 2: 90Y-anti-CD25 radioimmunoconjugate combined with BEAM conditioning for AHCT in patients with relapsed/refractory Hodgkin lymphoma (aTac-BEAM trial).

Project 4: Novel nucleotide-based approaches targeting the STAT3 pathway for the treatment of lymphoma

Hua Yu & Marcin Kortylewski (Scientific), Elizabeth Budde (Clinical)

Growing evidence links B cell lymphoma patients’ poor survival and immune suppression to persistent activation of signal transducer and activator of transcription 3 (STAT3). In ABC-DLBCL, genetic mutations augment Toll-like receptor 9 (TLR9)/MyD88 signaling, thereby leading to secretion of cytokines that induce STAT3 activation in lymphoma cells and in the tumor-associated immune cells, such as myeloid-derived suppressor cells (MDSCs). The autocrine and paracrine STAT3 activation in cancer cells and in the tumor-associated immune cells enhances lymphoma’s tumorigenic and tolerogenic potential. To overcome the challenge imposed by lack of pharmacological inhibitors of STAT3, we developed a strategy to deliver therapeutic siRNA specifically into myeloid and B cells, by physically linking siRNA to TLR9 ligands/agonists, CpG oligodeoxynucleotides (ODNs). We have demonstrated in multiple tumor models that local tumor treatment using CpG-STAT3siRNA silences STAT3, stimulating systemic antitumor immunity, in addition to inducing direct B-cell lymphoma tumor cell apoptosis and sensitivity to radiation therapy (RT). We propose to move CpG-STAT3siRNA to phase 1b clinical trials in NHL. In year 10 of the current SPORE, we included in the project a second generation STAT3 inhibitor: linking CpG to a high-affinity STAT3-DNA binding sequence called STAT3decoy ODN (dODN), which effectively competes STAT3 DNA binding. Compared to CpG-STAT3siRNA, CpG-STAT3dODN exhibits improved nuclease-resistance which allows for systemic administration and treatment of advanced, disseminated lymphomas. We anticipate that with the clinical testing of the first CpG-STAT3siRNA strategy together with RT in the local setting, and with the optimization of new CpG-STAT3dODN for systemic administration, the proposed studies will accelerate development of novel, effective and safe nucleotide-based immunotherapeutic strategies for targeting intracellular STAT3 in NHL and potentially other hematologic malignancies.

Specific Aim 1: Conduct first-in-human phase Ib trial of intratumoral injection of CpG-STAT3 siRNA in combination with local radiation in B-cell non-Hodgkin lymphoma.

Specific Aim 2: Optimize the CpG-STAT3dODN strategy for targeting B cell lymphoma cells.

Core A: Administrative

Core Leaders: Stephen Forman/Larry Kwak/Sandra Thomas

The Administrative Core directly supports management of SPORE projects, cores, and funds. The Core will coordinate SPORE-related meetings, preparing and submitting annual progress reports, and make decisions regarding selection and support of the best and most promising projects. Importantly, the Administrative Core will be responsible for the oversight of the Developmental Research and Career Development Programs in the Lymphoma SPORE. Finally, the Core will also promote patient interests and equitable access to treatment on SPORE studies by working with a patient advocate to ensure that SPORE clinical studies are patient-centered.

Core B: Biostats

Joycelynne Palmer / Joyce Niland

Core B, the Biostatistics and Research Informatics Core of the City of Hope Lymphoma SPORE, provides information management and statistical expertise across all SPORE research activities, including study design, safety monitoring, data collection, data quality assurance, data analysis, and multicenter study site coordination. Core B will ensure that the proposed research hypotheses will be addressed with appropriate measures, tests, and interpretation, whether the data arise from genomic studies, basic science, translational, immunologic studies, or clinical trials. The centralized, comprehensive, and integrated framework of Core B assures each SPORE investigator access to statistical and informatics experts who have appropriate experience, interests and time to engage in the collaborative development of study designs, analysis plans, data analysis, interpretation, reporting, and abstract/manuscript preparation.

Core B will also provide infrastructure for the management and integration of both existing and newly collected data and specimens through consistent and compatible data handling. The Core plays an integral role in the scientific development, execution, and analysis of all projects in the SPORE. Core B investigators have extensive experience in quantitative methods for biomedical applications, including clinical, basic, and translational science studies, with particular expertise in hematologic malignancy research. Core B is committed to collaboration to help ensure the scientific integrity of the SPORE investigations, by participating in regular Project and Program meetings, and providing rigorous and innovative input on all statistical and information management matters arising within the projects.

The specific aims of Core B are as follows:

Specific Aim 1. To support high quality data management through state-of-the-art information technologies, ensuring standardization, quality assurance, security, training, monitoring, data integration, decision support, reporting and multicenter coordination.

Specific Aim 2. To provide biostatistical support to the Projects, Cores and Programs, by consulting on the design, data monitoring, analysis, statistical modeling, visualization, interpretation, reporting and publication of data generated by SPORE activities.

Core C: Tissue Bank

John Chan and Guido Marcucci co-leaders

The overarching goals of this core is to provide high quality, well annotated and strictly quality controlled biospecimens for the projects, to develop and implement assays needed for the analysis of the biospecimensand to collaborate with Core B to build the informatics infrastructures to facilitate all aspects of research linkedto biospecimens.

Specific Aim 1 is to provide tissue banking and histology/pathology services. Specialized services will be performed according to the needs of the projects with the collection of leukapheresis specimens to generate CAR-T cells (Project 1); characterization of complex Hodgkin lymphoma and host cell populations through multispectral multiplexed immunofluorescence (mIF) phenotyping and gene expression profiling (GEP) (Project 3); cytogenetic and genomic characterization of lymphomas and the preparation of samples to generate primary patient-derived xenograft (PDX) non Hodgkin lymphoma models (Project 4).

Specific Aim 2: Because of the complexity of the datasets associated with the functions of Core C, we will collaborate with Core B (Research Informatics) to design, build, and integrate databases relevant to biospecimens to improve their functionality and connectivity to support SPORE projects and collaborations on other NCI-sponsored projects.

Core D: Manufacturing

Larry Kwak (overall) and David Horne (small molecule) co-leaders

The primary objective of Core D is to provide process development, regulatory support, and well-documented cGMP-compliant clinical-grade production of characterized CAR T cell products, monoclonal antibodies (mAb), lentivirus vectors, and complex small molecules, including nanomaterials, biopolymers (peptides, siRNA-aptamers, and DNA-peptide hybrids), and complex natural products. We will apply our established project management, product development, regulatory, and manufacturing capability to the benefit of SPORE investigators by providing assistance in pre-clinical development strategy, regulatory affairs, and process devolvement. Quality Assurance, product characterization, and compliance with regulatory requirements for process and product gained from our extensive history of cGMP manufacturing for clinical trials will ensure suitability, control, and scalability of the proposed clinical projects.

Career Enhancement Program (CEP)

Leaders: Stephen J. Forman, Michael Caligiuri, Smita Bhatia

The primary objective of the CEP is to attract and train quality investigators to the field of lymphoma translational research. This program will support, both financially and scientifically, junior or established investigators at City of Hope and University of Alabama Birmingham (UAB) who want to focus or refocus their research careers on lymphoma. Funds can also be used to recruit investigators who plan to pursue a career in lymphoma research to City of Hope and/or Beckman Research Institute, or University of Alabama. The CEP supports two individuals per year. SPORE has budgeted $50,000 per year direct costs for this program with an additional contribution of $100,000 per year from City of Hope and $25,000 from UAB. City of Hope is administering the program, in which UAB is participating. Award recipients can use funds for salary support for protected research time, for research project personnel or supplies, and for expenses related to meetings and training. Awardees will be supported for a period of up to two years.

Developmental Research Program (DRP)

Leaders: Larry Kwak, John Chan, Ravi Bhatia

The purpose of the Developmental Research Program (DRP) is to identify and support first-rate, pioneering translational projects in lymphoma that, despite their potential, are not yet mature for full program status. All members of the research community at City of Hope and University of Alabama Birmingham (UAB) are encouraged to consider the opportunity. We have requested $50,000 per year to support this program, and City of Hope and UAB will match these funds annually by $100,000 and $25,000, respectively. At least two researchers per year receive awards, which are granted for up to two years. Funds can be devoted to research supplies and minor equipment, personnel costs, and relevant meeting expenses. Promising investigations may replace SPORE research projects that have either acquired funding as independent R01/P01 projects, or those that have not satisfactorily progressed.