A significant component of the therapeutic effect of allogeneic hematopoietic stem cell transplantation (alloHSCT) is mediated by T cells in the allograft (i.e. graft-versus-tumor [GVT] effect). However, the degree to which GVT effect contributes to the efficacy of alloHSCT differs significantly between various malignancies. In extremely chemotherapy-refractory patients, the GVT effect may be insufficiently potent to be detectable because the tumor growth rate exceeds the ability of the immune effect to eliminate disease. The susceptibility of various malignancies to the GVT effect most likely reflects the biologic characteristics that are unique to that respective disease, such as growth rate or antigen expression. Due to this significant heterogeneity, we elected to focus our research efforts, relative to GVT effects, on two disease groups, breast cancer and B cell malignancies. A. Vaccination of normal donors with idiotype vaccines Two major limitations of allogeneic cellular therapy are that the immunologic effects can be non-specific and the GVT effects are often insufficient to eradicate disease. The utilization of tumor-specific vaccines along with allogeneic cellular therapy may enhance both the specificity and the potency of the GVT in selected tumors. Multiple myeloma, as well as other B cell malignancies, synthesizes a single immunoglobulin (Ig) with unique variable regions, referred to idiotypes (Id) in the heavy and light chains. The idiotypic determinants of the surface Ig of myeloma can thus serve as a tumor-specific marker for the malignant clone. It was our hypothesis that the vaccination of normal allogeneic stem cell donors with patient-derived Id-specific vaccine would generate Id-specific immunity and be passively transferred to the recipient at the time of transplant thereby reducing the risk of relapse in patients with multiple myeloma. In collaboration with the Kwak and Neelapu laboratories at the M.D. Anderson Cancer Center, we designed a protocol, 00-C-0102, which combined Id vaccines and our targeted lymphocyte depletion approach with alloHSCT for the treatment of multiple myeloma. The goal of this protocol was to transfer tumor antigen-specific immunity induced in the stem cell donor to the alloHSCT recipient to reduce relapse. Vaccine was generated from patient-derived Id conjugated to an immunogenic protein carrier, keyhole limpet hemocyanin (Id-KLH). Allogeneic stem cell donors are vaccinated prior to stem cell donation to study the adoptive transfer of vaccine-primed lymphocytes. Ten patients and their respective donors have been enrolled onto study. Vaccine was successfully generated from all 10 patients, and all 10 donors completed vaccinations without significant complications;grade 3 toxicities, which were transient, were noted in only two donors. Study data demonstrated that tumor specific immunity could be induced in donors and suggest that immunity was passively transferred to the recipient. It is our intent to utilize this strategy in other B cell malignancies, such as follicular NHL, from which Id vaccine can be generated. B. Develop novel treatment strategies for patients with persistent or recurrent disease after allogeneic adoptive cellular therapy The management and treatment of relapse or progression of disease following alloHSCT is a significant clinical problem. Treatment options are extremely limited for patients who experience disease recurrence or progression following alloHSCT. These options include the withdrawal of immune suppression and/or the administration of donor lymphocyte infusions (DLI), the use of conventional therapeutic treatments for the respective disease, or a second alloHSCT. With the exception of chronic phase chronic myelogenous leukemia, these treatments only benefit a minority of patients, the benefits are often transient, and the treatments are associated with a high degree of morbidity, particularly GVHD. In addition, many of these therapies are not applicable to patients in whom disease recurs while experiencing active GVHD. After alloHSCT, lymphocytes are found infiltrating residual tumor. It is likely that these cells are of donor origin and may exhibit enhanced antigen specificity and tumor-specific homing. Compared to donor peripheral blood lymphocytes or to tumor-infiltrating lymphocytes in non-transplant patients, the lymphocytes found in tumor after alloHSCT may have a higher potential for disease control. It was our hypothesis that lymphocytes found in tumor after alloHSCT are of donor origin, and because they are tumor-derived, they may be tumor-specific in their homing and antigen specificity characteristics. Further, activation and expansion of these cells through CD3/CD28 costimulation may yield a more effective form of cell therapy after alloHSCT, with enhanced GVT effects and less GVHD. Pre-clinical studies of the costimulation technique were evaluated using autologous lymphocytes derived from a variety of tumor types (i.e. from anonymous patients having tumor resected for clinical indications). A two-week culture with CD3/CD28 costimulation resulted in up to 30-fold increase in T cell numbers. Several important observations were made during these pre-clinical studies. The first was the addition of tumor to the culture resulted in 3- to 10-fold better yield of T cells as compared to cultures without tumor cells, suggesting the possibility of antigen-driven expansion. Second, an additional round of cell costimulation yielded additional 10-fold expansion. Third, in cultures containing tumor cells, tumor cell death was observed, suggesting either T-cell mediated killing and/or the culture conditions were not conducive to tumor cell growth. Fourth, costimulation and culture yielded a cell production with an effector memory cell phenotype and minimal numbers of cells with a T-regulatory phenotype. Based on these pre-clinical data, a protocol, 07-C-0064, for the clinical use of allogeneic TDL for treatment of B-cell malignancies which have relapsed after alloHSCT was written and aand subsequently received FDA IND approval in January 2007. The primary objective of the study is to evaluate the feasibility of administering ex-vivo costimulated/expanded TDL in patients with persistent or recurrent BCL following alloHSCT. Specific feasibility aims include the consistent isolation, costimulation and expansion of clinically relevant numbers of TDL from resected tumor specimens. The other primary aim is to determine the safety of administering TDL relative to infusion toxicities and hyperacute GVHD. The protocol has a number of correlative studies which include both tumor and lymphocyte characterization prior to culture and characterization of the immune phenotypic and functional characteristics of TDL after culture. In addition attempts will be made at target antigen discovery, through SEREX-related methods for the identification of tumor-reactive donor T cell targets.
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| van den Brink, Marcel R M; Porter, David L; Giralt, Sergio et al. (2010) Relapse after allogeneic hematopoietic cell therapy. Biol Blood Marrow Transplant 16:S138-45 |
| Baskar, Sivasubramanian; Suschak, Jessica M; Samija, Ivan et al. (2009) A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display. Blood : |
| Bishop, M R; Dean, R M; Steinberg, S M et al. (2008) Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation. Ann Oncol 19:1935-40 |
