Results from an analysis presented at the 2015 ASH Meeting on Hematologic Malignancies confirm that T-cell exhaustion and senescence (occurring when T cells are chronically activated at sites of chronic inflammation) is a distinguishing feature of relapse among patients with multiple myeloma who have undergone autologous stem cell transplant (ASCT).
These results support early introduction of immunotherapy to stimulate antitumor immunity after ASCT, however, development of these interventions requires a comprehensive understanding of the immunologic milieu in the tumor microenvironment – which is currently lacking, according to David J. Chung, MD, PhD, from the Department of Medicine and Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center in New York, and colleagues.
"Multiple myeloma is the most common indication for high-dose chemotherapy and ASCT," Dr. Chung and co-authors wrote. "Post-transplant lenalidomide maintenance therapy doubles progression-free survival, but almost all patients eventually relapse." There is, then, a need for post-transplant immunotherapy to restore antitumor immunity to target residual disease and improve outcomes in these patients."
To provide more information that could help guide optimal timing of immunotherapy and identify potential markers of relapse, Dr. Chung and colleagues evaluated lymphocyte composition and function in 55 patients with multiple myeloma who underwent ASCT. Dr. Chung presented the findings in an oral abstract presentation at the 2015 ASH Meeting on Hematologic Malignancies.
Patients were evaluated for one year; peripheral blood was obtained before ASCT and 11, 30, 90, 180, and 365 days after ASCT. If a patient experienced relapse, peripheral blood was collected at that time.
In the study, leukocyte concentrates were used as a source of healthy donor cells; mononuclear cells were analyzed by flow cytometry for phenotypic assessment of lymphocyte subset composition. Functional assessment of dendritic cell and T-cell activity in vitro was assayed in autologous and allogeneic mixed leukocyte reactions, cytotoxic T lymphocyte lysis assays, and PD-1 blockade experiments.
Dr. Chung and investigators found that CD3+, CD4+, CD25bright, and CD127neg regulatory T cells declined as CD8+ T cells expanded during early lymphocyte recovery post-ASCT. "[This decline] markedly reduces the ratio of regulatory T cells to CD8+ effector T cells and provides a critical early window for the introduction of immune-based, post-transplant consolidation therapies," the researchers wrote.
CD8+ T cells, they added, responded to autologous dendritic cells presenting tumor antigen in vitro as early as 12 days after transplant, demonstrating preservation of cellular reactivity.
Dr. Chung and investigators also identified a subpopulation of exhausted/senescent CD8+ T cells that downregulated CD28 and upregulated CD57 and PD-1 – characterizing immune impairment and relapse after ASCT. Notably, relapsing patients also had higher numbers of CD8+CD28-PD-1+ T cells at three months post-transplant, but before detection of clinical disease, indicating that higher levels of these T cells could identify patients at risk of relapse.
Chung DJ, Pronschinske KB, Shyer JA, et al. T cell exhaustion/senescence and relapse in multiple myeloma after autologous stem cell transplantation. Abstract #2. Presented at the 2015 ASH Meeting on Hematologic Malignancies; September 18, 2015; Chicago, IL.