Tumor-Infiltrating Lymphocytes Are Present in Cancer Relapse After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT), of Donor Origin, Distinct From Peripheral Blood Donor Lymphocytes and Exhibit Effector Function With CD3/CD28 Costimulation Ex-Vivo
Year: 2011
Type: article
Abstract: We theorized that in patients with persistent or relapsed cancer following alloHSCT, tumor would be a source of tumor-reactive donor T lymphocytes that could be expanded ex vivo to provide a potent T cell therapy. We recently reported our initial clinical results demonstrating feasibility, safety and biologic activity of this approach in patients with refractory B cell tumor relapse after alloHSCT (ASH 2010). We report here the characterization of the initial tumor infiltrate as compared to circulating T cell populations, and as compared to expanded products from tumor and blood. We determined that tumor-infiltrating donor T cells (confirmed by chimerism assays) differed from peripheral donor T cell populations in individual patients in terms of T cell frequency, naïve/memory phenotype, ratio of CD4:CD8 cells and frequencies of effector and regulatory T cell populations. Following α-CD3/CD28 antibody-coated bead expansion with low dose IL-2, PCR-based chimerism assessment of products demonstrated that the costimulated lymphocytes were of donor origin; by flow, products were greater than 95% CD3+ T cells. CD4+ T cells usually predominated, but there was significant patient variation in expansions from both tumor infiltrates and blood. Both expanded tumor and blood products demonstrated increased expression of markers of activation and effector function (CD4: CD40L; CD8: CD137, perforin, NKG2D). The proportion of FoxP3+ Treg cells declined and IFN-producing TBet+ Th1/Tc1 effectors became the dominant T cell population. While the percentage of cells expressing CD27 and CD28 declined proportionate to the duration of culture, their expression was retained in a significant proportion of cells after our typical 12-day culture. Our findings support the hypothesis that, after allotransplant, donor lymphocytes can be identified in residual/progressing tumor, and appear to be distinct from circulating T cell populations. Furthermore, these tumor-infiltrating T cells can be effectively expanded, even from minor populations, to become T-Bet+ T effectors, plausibly circumventing a mechanism of GVL resistance. Costimulated tumor-derived donor lymphocytes may be a therapeutic option for patients without a source of, or who have not responded to, donor lymphocyte infusion for disease progression after alloHSCT.
Institutions: National Institutes of Health, National Cancer Institute
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2026571014