Journal of Cell Science & Therapy
Open Access

Immunotransplant for mantle cell lymphoma: Phase I/II study preliminary results

International Conference & Exhibition on Cell Science & Stem Cell Research

29 Nov - 1 Dec 2011 Philadelphia Airport Marriott, USA

Joshua D Brody, Debra Katherine Czerwinski, Victoria Carlton, Martin Moorhead, Jianbiao Zheng, Mark Klinger, Malek Faham, Ranjana Advani, Holbrook E Kohrt, Arash Alizadeh, Robert S Negrin, Kevin Sheehan and Ronald Levy

Scientific Tracks Abstracts: J Cell Sci Ther

Abstract :

Mantle cell lymphoma (MCL) has a poor long-term prognosis. Th ough autologous transplant prolongs survival, novel and mechanistically distinct therapies are needed to target residual, myeloablation-resistant tumor cells that result in relapse. Trials of CpG-based vaccines for low-grade lymphoma have shown induction of anti-tumor T cells and clinical responses. In a pre-clinical model, we developed the immunotransplant maneuver combining: 1) CpG-based vaccination, 2) harvest of vaccine-primed T cells, 3) myeloablation with stem cell rescue, and 4) T cell re-infusion. Immunotransplant amplifi es the proportion of anti-tumor T cells by an order of magnitude and cures even bulky, systemic lymphoma burden Methods: We initiated a phase I/II study of immunotransplant for newly diagnosed MCL patients to test the hypothesis that immunotransplant will amplify anti-tumor T cells as in the pre-clinical model. Anti-tumor T cells are assessed by co-culturing autologous tumor with peripheral blood T cells and measuring their production of: IFNg, TNF, IL2, CD137, perforin and granzyme by multiplex surface and intracellular fl ow cytometry. A secondary endpoint is measurement of molecular residual disease (MRD) using both standard allele-specifi c oligonucleotide (ASO) qPCR as well as high-throughput sequencing (HTS) of the entire IgH repertoire. Th e study is powered to detect a 50% improvement in sustained molecular remission rate compared to recent trials of standard transplant . Using the same HTS technology, we have also initiated studies of the entire TCRβ repertoire as an alternate approach of tracking the amplifi cation of vaccine-induced T-cells. Results: Accrual has been rapid with 25 patients enrolled in 22 months and 13 patients completing the complete protocol so far. Flow-cytometric immune response testing has demonstrated that immunotransplant amplifi es the proportion of tumor-reactive T cells in 83% of patients thus far. Notably, we have observed some patients with primarily CD8 T cell responses, some with CD4 T cell responses, and some with a combination of the two. In some cases, tumor-reactive T cells have been tested for reactivity to autologous, non-malignant B cells and have demonstrated a signifi cant proportion that are tumor-specifi c. TCRβ repertoire sequencing has also demonstrated instances of signifi cant clonal amplifi cation aft er immunotransplantation, some exceeding three orders of magnitude. In extreme cases, these have yielded dominant clones comprising as much as 50% of a patient?s entire peripheral blood T cell repertoire post-transplant. HTS of the IgH repertoire has been an eff ective measurement of MRD bypassing the assay individualization of ASO qPCR and has been shown to be more sensitive than conventional fl ow cytometry. Conclusions: Pre-clinically, amplifi cation of anti-tumor T cells correlates with cure of even myeloablation-resistant disease. Th e reiteration of anti-tumor T cell amplifi cation in our preliminary patient data raises the possibility that immunotransplant may improve clinical outcomes. Ongoing MRD testing should suggest whether certain patterns of T cell response ?measured functionally per fl ow cytometry or clonally per HTS- correlate with clinical benefi t and whether the cohort has a better-than-expected molecular remission rate