We propose a novel cellular therapy to address the problems of opportunistic viral infection and relapse of B-lineage malignancies after haploidentical stem cell transplantation (Haplo SCT). Viral infections remain a significant cause of failure in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Recipients of Haploidentical (Haplo) donor grafts are at particular risk because of the T-cell depletion required to prevent graft versus host disease (GvHD). Antiviral drugs are effective only for some viruses, and most have significant toxicities. Our center has developed a novel approach that effectively expands cytotoxic T lymphocytes (CTL) specific for cytomegalovirus, Epstein-Barr virus and adenoviruses from T- cells in a single culture. Adoptive transfer of these multivirus-specific CTL (MV-CTL) from stem cell donors (including Haplo donors) has proved safe and highly effective in vivo. However, relapse remains a significant problem after Haplo SCT especially for patients with B-cell malignancies. Therefore, we have designed a chimeric antigen receptor (CAR) to redirect antigen specificity of T cells to the B cell lineage-restricted cell- surface molecule CD19. We hypothesize that the incidence of viral infection and relapse following Haplo SCT can be reduced by adoptively transferred donor-derived MV-CTL, genetically modified to be specific for the CD19 molecule expressed by tumor cells.
In Aim 1 we will conduct a Phase II randomized clinical trial in which we will give CAR-CD19-1- MV-CTL or no CTL to patients with CD19-I- malignancies who have received a Haplo SCT.
In Aim 2, we will delineate; (i) the magnitude and duration of persistence and (ii) the anti-viral and anti-leukemic effects of adoptively transferred CTL. In aggregate, the results of the studies will facilitate the evolution of targeting post-HapIo SCT MRD with viral- and CD19-specific CTLs for enhanced disease- free survival of patients with B cell malignancies. Our proposal is feasible since our center has extensive experience developing, implementing and completing complex biological therapies with cell and gene therapy products and has successfully sponsored and implemented over 40 cell and gene therapy studies under more than 25 investigator initiated INDs, including Phase II multicenter studies .

Public Health Relevance

Infection and relapse of leukemia are unfortunately common complications of haploidentical stem cell transplant. This grant application will test whether immune cells (T cells) can be generated that are specific for virus and leukemia/lymphoma and infused to prevent infection and relapse. This will be part of the CTN effort to both develop and implement new therapies for recipients of allogeneic stem cell transplants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
4U10HL108945-06
Application #
9069027
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Di Fronzo, Nancy L
Project Start
2011-08-08
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Steering Committee Of The Blood And Marrow Transplant Clinical Trials Network (2016) The Blood and Marrow Transplant Clinical Trials Network: An Effective Infrastructure for Addressing Important Issues in Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1747-1757
Appelbaum, Frederick R; Anasetti, Claudio; Antin, Joseph H et al. (2015) Blood and marrow transplant clinical trials network state of the Science Symposium 2014. Biol Blood Marrow Transplant 21:202-24
Jacobsen, Paul B; Le-Rademacher, Jennifer; Jim, Heather et al. (2014) Exercise and stress management training prior to hematopoietic cell transplantation: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902. Biol Blood Marrow Transplant 20:1530-6
Weber, Gerrit; Caruana, Ignazio; Rouce, Rayne H et al. (2013) Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy. Clin Cancer Res 19:5079-91
Horwitz, Edwin M; Horowitz, Mary M; DiFronzo, Nancy L et al. (2011) Guidance for developing phase II cell therapy trial proposals for consideration by the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant 17:192-6
Kohn, Donald B; Dotti, Gianpietro; Brentjens, Renier et al. (2011) CARs on track in the clinic. Mol Ther 19:432-8
Xing, Dongxia; Ramsay, Alan G; Gribben, John G et al. (2010) Cord blood natural killer cells exhibit impaired lytic immunological synapse formation that is reversed with IL-2 exvivo expansion. J Immunother 33:684-96