Showing papers by "Malcolm K. Brenner published in 2011"

Inducible apoptosis as a safety switch for adoptive cell therapy

Abstract: Background Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. Methods We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Results Five patients between the ages of 3 and 17 years who had und...

CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients

Abstract: Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the ζ-endodomains, while the other encoded only the ζ-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.

Methods for inducing selective apoptosis

Abstract: Provided herein are methods for cell therapy by modifying transfused cells to express an inducible caspase 9 protein, so that the cells may be selectively killed if the patient experiences dangerous side effects. Provided also within relates in part to methods for preventing or treating Graft versus Host Disease by modifying T cells before administration to a patient, so that they may be selectively killed if GvHD develops in the patient.

Immunotherapy of cancer using genetically engineered GD2-specific T cells

Abstract: The present invention concerns immunotherapy for cancers having cells that comprise the ganglioside GD2 antigen. In specific embodiment, T cells having a chimeric receptor that targets GD2 is employed. In particular cases, the chimeric receptor comprises antibody, cytoplasmic signaling domain from the T cell receptor, and/or costimulatory molecule(s).

Children with acute leukemia: a comparison of outcomes from allogeneic blood stem cell and bone marrow transplantation.

Abstract: Background The relative merits of peripheral blood stem-cell transplantation (PBSCT) versus bone marrow transplantation (BMT) for children with standard and high-risk hematologic malignancies remain unclear. In a retrospective study, we compared allogeneic PBSCT (n = 30) with BMT (n = 110) in children with acute leukemia between January 2001 and September 2006. Procedure Median age for PBSCT was 9 years versus 8 years for BMT. Descriptive statistics were used to summarize the demographic and medical variables. The unadjusted probabilities of disease-free survival were estimated using the Kaplan–Meier method. The association of graft-source and time to each of the study endpoints was estimated by Cox's regression model and the occurrence of graft-versus-host disease (GvHD) was included as a time-dependent covariate. Results Time to neutrophil engraftment and platelet independence was faster after PBSCT than BMT (neutrophils 15.0 days vs. 17.0 days, P < 0.001; platelets, 21.0 days vs. 27.0 days, P = 0.034). The cumulative incidence of grades II–IV acute GvHD at 100 days was 10.4% (SE 5.6%) after PBSCT and 15.1% (SE 3.5%) after BMT (P = NS). The cumulative incidence of chronic GvHD was 13.8% (SE 6.3%) after PBSCT and 11.3% (SE 3.1%) after BMT (P = NS). One-year disease-free survival was 37.9% (SE 9.0%) for PBSCT recipients versus 65.1% (SE 4.6%) after BMT (P = 0.005) but this difference was not sustained in multivariate analysis. Thus, only disease risk and pre-transplant CMV seropositivity were significant predictors of disease-free survival. Conclusions We conclude that PBSCT for children produces faster engraftment without increased risk of acute or chronic GvHD. Pediatr Blood Cancer. 2010;56:143–151. © 2010 Wiley-Liss, Inc.

Highlights of the second international conference on "immunotherapy in pediatric oncology"

Abstract: The Second International Conference on Immunotherapy in Pediatric Oncology was held in Houston, Texas, USA, October 11-12, 2010, to discuss the progress and challenges that have occurred in cutting edge immunotherapeutic strategies currently being developed for pediatric oncology. Major topics included immune targeting of acute lymphoblastic leukemia and pediatric solid tumors, chimeric antigen receptors (CARs) for hematologic malignancies and solid tumors, enhancing graft-versus-leukemia for pediatric cancers, overcoming hurdles of immunotherapy, strategies to active the innate immune system, and moving immunotherapy beyond phase I studies. Significant progress has been made in the last 2 years both in the development of novel immunobiologics such as CARs, and in establishing survival benefits of an anti-GD2 monoclonal antibody in randomized studies. Although there is much excitement going forward, a great deal of laboratory and regulatory challenges lie ahead in improving the efficacy of each of these modalities as well as getting them to patients in a timely and cost-effective fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies.

Extending the Use of Adoptive T Cell Immunotherapy for Infections and Cancer

Abstract: Adoptive transfer of antigen-specific T cells has proven to be an effective and powerful therapeutic tool in the prevention and treatment of viral infections (e.g., cytomegalovirus [CMV], Epstein-Barr virus [EBV], and adenovirus) and virus-associated diseases, such as EBV-associated lymphoproliferative disease (LPD), that arise in the immunocompromised host. This therapeutic approach has also been extended to the treatment of cancer and has shown some success in patients with melanoma and EBV-associated malignancies such as Hodgkin’s lymphoma and nasopharyngeal carcinoma. However, this strategy has been less successful in other malignancies. To improve the efficacy of adoptively transferred tumor-reactive T cells, a number of groups have sought to identify better immunotherapeutic target antigens and to design protocols for the optimal in vitro propagation of tumor-reactive T cells, which are often otherwise anergized or tolerized. Another approach that has recently come to fore involves the genetic modification of T cells using genes that confer properties such as new antigen specificity, improved homing to tumor sites, or increased resistance to tumor immune evasion. This chapter evaluates recent advances in tumor immunotherapy, including T cell engineering, and speculates on the future potential of adoptive T cell transfer in the field of cancer therapy.

Immunotherapy of non-small lung cancer using genetically engineered gd2-specific t cells

Abstract: The present invention concerns immunotherapy for brain cancers having cells that comprise the ganglioside GD2 antigen. In specific embodiment, T cells having a chimeric receptor that targets GD2 is employed, the chimeric receptor comprises antibody, cytoplasmic signaling domain from the T cell receptor, and costimulatory molecule(s).