Baylor College of Medicine SPORE in Lymphoma
Baylor College of Medicine
Principal Investigator(s):
Helen Heslop, MD
Malcolm K. Brenner, MD, PhD
- Principal Investigators Contact Information
- Overview
- Project 1: Immunotherapy of B-Cell Lymphoma with Natural Killer T Cells
- Project 2: CAR-T Cell Therapy for T Cell Lymphoma
- Project 3: Increasing the Potency and Accessibility of EBVSTs for the Treatment of Lymphoma
- Administrative Core
- Clinical Research and Biostatistics Core
- GMP Cell and Vector Production Core
- Biospecimen and Pathology Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigators Contact Information
Helen Heslop, MD
Director, Center for Cell and Gene Therapy
Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital
1102 Bates Street, Suite 1640.04
Houston, TX 77030
Tel: 832-824-4662
Malcolm Brenner, MD, PhD
Founding Director, Center for Cell and Gene Therapy
Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital
Institution
1102 Bates St, Suite 1640.06
Houston, TX 77030
Tel: 832-824-4663
Overview
The long-term goal of the Baylor College of Medicine and Houston Methodist Hospital Lymphoma SPORE is to develop in the laboratory and test in the clinic novel cellular immunotherapies to treat non-Hodgkin lymphoma and Hodgkin lymphoma. We have assembled an integrated team of laboratory scientists and clinical investigators with strong track records of productive translational research. To address the persistent challenges of suboptimal long-term lymphoma control and unacceptable rates of treatment-related toxicity in lymphoma, investigators in this program have proposed three projects, each involving early-phase clinical trials:
Project 1: Immunotherapy of B-Cell Lymphoma with Natural Killer T Cells
Project 2: CAR-T Cell Therapy for T Cell Lymphoma
Project 3: Increasing the Potency and Accessibility of EBVSTs for the Treatment of Lymphoma
Successful completion of these studies should increase the potency and improve accessibility of several strategies with genetically modified immune effector cells for lymphoma. These Projects are supported by Administrative, Biospecimen and Pathology, GMP Cell and Vector Production, and Clinical Research and Biostatistics shared core resources. In addition, our Developmental Research Program is designed to support pilot projects of novel translational ideas in lymphoma research with the long-term goal of incorporating these projects into the SPORE or seeking independent funding for them in the future. Supporting the future of translational lymphoma research, our Career Enhancement Program will provide training in translational research in lymphoma for a diverse group of young investigators or established investigators who wish to refocus their career on lymphoma.
Project 1: Immunotherapy of B-Cell Lymphoma with Natural Killer T Cells
Project Co-Leaders:
Leonid Metelitsa, MD, PhD (Basic Project Leader)
Carlos Ramos, MD (Adult Clinical Project Lead)
Carl Allen, MD, PhD (Pediatric Clinical Project Lead)
The long-term goal of this Project is to develop a safe and effective immunotherapy for CD19+ non-Hodgkin lymphoma (NHL) using natural and engineered properties of natural killer T cells (NKTs). Recent clinical trials have demonstrated that T cells redirected against the CD19 antigen using a CD19-specific CAR can induce sustained complete responses in adult and pediatric patients with refractory B-cell malignancies, leading to licensed products now in routine clinical use. However, this therapy is limited by production failures in some patients, disease recurrence and expense. Project 1 investigators hypothesize that banked third-party NKTs engineered to express CD19.CAR will combine the natural antitumor properties of NKTs with synthetic CAR-mediated killing of CD19-expressing lymphoma cells. Moreover, NKT are likely to provide benefit with less toxicity, enabling us to generate a therapeutic product immediately available for all eligible patients. They have generated a bank of third-party NKTs genetically modified to express a CD19.CAR and IL15 and initiated a clinical trial to test the safety and antitumor efficacy of this product in NHL patients. The initial clinical results are promising with tumor responses in 3 of 4 patients including a complete response. If safety and responses continue to be observed during dose escalation, industry partner Athenex will move this approach to multicenter testing. They will then initiate a follow up study testing a new construct expressed in banked allogeneic NKT cells and tested in a follow-up CAR.19 NKT trial in the SPORE. In preclinical studies, they will extend observations that LEF1 transcriptional activity supports functional fitness, reduces exhaustion, and increases the anti-tumor activity of NKT cells. They also will evaluate if LEF1 transgenic overexpression in CAR-NKTs enhances in vivo expansion/persistence, tumor localization, and anti-tumor efficacy without causing toxicity.
Project 2: CAR-T Cell Therapy for T Cell lymphoma
Project Co-Leaders:
Malcolm Brenner, MD, PhD (Clinical Project Leader, IND sponsor)
Maksim Mamonkin, PhD (Basic Project Leader)
Norohiro Watanabe, PhD (Basic Co-investigator)
LaQuisa Hill, MD (Adult Clinical Project Lead)
Rayne Rouce, MD (Pediatric Clinical Project Lead)
The long-term goal of this Project is to extend the benefits of CAR-T cells to T-cell lymphoma, where there is an unmet clinical need. In the previous funding period, investigators conducted a first-in-man Phase I clinical trial of patient-derived CD5 CAR T-cells where they observed complete or partial responses in 44% of patients with treatment-resistant peripheral T cell lymphoma with a favorable safety profile. In the renewal, they propose to enhance the efficacy of CD5 CAR T-cells by ensuring the cell product retains minimally differentiated CAR T populations, which possess the highest expansion potential and superior lymph-node homing properties. They also amended the manufacturing protocol to improve the frequency of naïve-like and central memory T-cells and thus superior anti-tumor activity. In addition, they modified the clinical protocol to allow a CD5 CAR T-cell product made from the stem cell donor to be used in patients who relapse post allograft, as T cells derived from healthy donors generally function better than T cells obtained from heavily pretreated patients. In general, the combination of rapid disease progression and delays in manufacturing individualized products can profoundly impede access to this therapy. The investigators will therefore develop banked CD5 CAR T-cells with immediate availability allowing rapid treatment. They have established an allogeneic CAR T-cell platform based on TCR-edited healthy T-cells to prevent graft versus host disease. To protect these edited cells from immune rejection by the recipient, they will use the 4-1BB specific chimeric alloimmune defense receptor (ADR) developed in their last funding period. The ADR enables donor-derived CAR T-cells to recognize and eliminate activated alloreactive host T-cells. After generating banked allogeneic TCR-edited CD5 CAR T-cells armed with a 4-1BB ADR, they will initiate a Phase I clinical trial in patients with relapsed T cell lymphomas.
Project 3: Increasing the Potency and Accessibility of EBVSTs for the Treatment of Lymphoma
Project Co-Leaders:
Cliona Rooney, PhD (Basic Science Leader)
Helen Heslop, MD (Adult Clinical Project Lead)
Bilal Omer, MD (Pediatric Clinical Project Lead)
In the current funding period, investigators undertook a trial of EBV-specific T-cells (EBVSTs) in patients with EBV+ lymphoma, optimized manufacturing, and broadened their repertoire to enhance the tumor-specificity of the product. The next trial will start in the last year of this funding period, and they aim to enhance in vivo proliferation and persistence of functional EBVSTs by expressing a constitutively active IL7 receptor (C7R) that may also provide resistance to an immunosuppressive tumor microenvironment. In preclinical models, transfer of C7R to T cells upregulates expression of their anti-apoptotic molecules, prolongs proliferation and tumor cell killing, and enhances anti-tumor activity in vivo. In a study led by Dr. Omer, C7R-modified GD2.CARTs proved safe and produced tumor responses in patients with neuroblastoma. In preclinical studies, they will evaluate if a histone deacetylase inhibitor simultaneously increases antigen stimulation of C7R-EBVST by lymphoma cells while increasing susceptibility of these tumor cells to C7R-EBVST killing. In addition, histone deacetylase inhibitors should increase tumor cell sensitivity to cytotoxic effector cells by increasing the expression of pro-apoptotic caspases. Finally, to provide an immediately available EBVST product, investigators will generate a bank of highly characterized C7R-EBVSTs from healthy donors. Because EBVSTs are virus-specific rather than allo-reactive, the product should not induce graft versus host disease. To prevent rejection of these third-party engineered T cells, the investigators will express a CD30.CAR that pre-clinical studies show eliminates alloreactive T-cells.
Administrative Core
Core Directors:
Helen Heslop, MD
Malcolm Brenner, MD, PhD
The Administrative Core supports the leadership of the overall Lymphoma SPORE to facilitate cooperation and communication between all Projects and Cores for the successful completion of the proposed research. We provide projects with centralized administrative and clinical trial support, arrange internal group meetings and External Advisory Board meetings, and assist each project and core leader with budgetary issues. This Core will also manage interactions and collaborations with local and national resources, as well as coordinating input from patient advocates and the Baylor College of Medicine Office of Diversity.
Clinical Research and Biostatistics Core
Core Director(s):
Helen Heslop, MD
Bambi Grilley
Tao Wang, PhD
The Clinical Research and Biostatistics Core supports the SPORE clinical research studies to ensure they are conducted safely, accurately and in accordance with applicable regulations. This Core also provides all SPORE projects with statistical support for preclinical experiments and clinical trials.
GMP Cell and Vector Production Core
Core Director(s):
Natasha Lapteva, PhD
Zhuyong Mei, MD
The Cell and Vector Production Core is essential for the clinical protocols proposed in each of the SPORE projects. The Core will be responsible for the preparation of therapeutic grade viral vectors and for manufacturing the various cellular therapy products that will be used in the proposed clinical trials. The Core will additionally assist in the translation of pre-clinical procedures into clinical scale manufacturing and testing. Further, the Core will provide the quality control and assurance services required to support the Good Manufacturing Practices infrastructure.
Biospecimen and Pathology Core
Core Directors:
Andrea Marcogliese, MD
Youli Zu, MD, PhD
The goal of the Biospecimen and Pathology Core is to provide high quality tissue and blood samples from lymphoma patients to investigators undertaking translational research studies in lymphoma. The Core pathologists also provide support to the clinical trials in this SPORE by reviewing tissue and performing staining and other molecular tests for target antigens.
Developmental Research Program
Program Directors:
Malcolm Brenner, MD, PhD
Margaret Goodell, PhD
George Carrum, MD
The goal of the Developmental Research Program (DRP) is to attract researchers from a wide range of fields to focus their expertise on lymphoma. We have used our matching funds for this program to bring new investigators into the SPORE. We will continue to support pilot projects of novel translational ideas in lymphoma research with the long-term goal of incorporating these projects into the SPORE or seeking independent funding for them in the future, while increasing diversity among our DRP awardees.
Career Enhancement Program
Program Directors:
Helen Heslop, MD
Martha Mims, MD, PhD
Siddartha Ganguly, MD
This Lymphoma SPORE’s Career Enhancement Program aims to increase the number of promising investigators working in this field in the future through tailored learning programs, expert mentorship, and individualized training in the translation of cell and gene therapies for lymphoma. We seek diverse young investigators or established scientists in other fields and select candidates based on their previous accomplishments and future potential impact on lymphoma research.