The immune deficiency that follows high dose chemotherapy and autologous hematopoietic progenitor cell transplantation (HCT) is well described. Antibody levels against infectious organisms steadily decline during the first year after transplantation, and early post-transplantation vaccination against preventable diseases is not recommended because the successful immunization rate is very low. As a consequence, opportunistic infections remain a major cause of morbidity and mortality after autologous HCT. The immune deficiency is even more pronounced in recipients of allogeneic HCT owing to the immune-suppression medication required to prevent graft-versus-host disease. Rapoport and colleagues now report a strategy that helps restore immunity in lymphopenic cancer patients receiving high-dose chemotherapy and autologous HCT.
In this clinical study, patients with advanced-stage multiple myeloma were treated with high-dose chemotherapy and autologous HCT. To overcome the immune deficiency associated with HCT, autologous T cells were harvested by apheresis, stimulated and expanded ex vivobefore transplantation, and transferred back to the patients at designated time points after HCT. The reconstitution of CD4+ and CD8+T-cell counts was significantly accelerated by an early post HCT T-cell infusion. A cohort of the study patients also received the 7-valent pneumococcal conjugate vaccine (PCV) 10 days prior to the collection of the autologous T cells. The infusion of the PCV-primed T cells shortly after transplantation combined with early post-transplant booster immunizations led to the induction of clinically relevant immunity within a month after transplantation. Immune assays showed that this group of patients had accelerated restoration of CD4+ T-cell function as T-cell proliferation in response to antigens including those not contained in the vaccine (staphylococcal enterotoxin B and cytomegalovirus antigens) was increased. Thus, combined pre-transplantation vaccine and early post-transplantation adoptive T-cell transfer with booster immunizations enables the development of enhanced memory T-cell responses.
This paper is important because it offers a platform to help restore impaired adaptive immunity in cancer patients. After high-dose chemotherapy and autologous HCT, innate immunity, composed of granulocytes, natural killer cells, and monocytes, is generally restored within a few weeks. Adaptive immunity, however, acquired over the individual's lifetime exposure to infections and vaccines, is lost as a result of the high-dose preparative regimen and is not overcome by the infusion of the memory B and T cells contained in the autologous graft. Rapoport and colleagues show that mature T cells in cancer patients can be ex vivo expanded, and that their infusions in the early post-transplant period accelerate the numerical recovery of T cells with a broad repertoire. The combination of antigen-primed T cells and early post-transplantation booster vaccinations led to enhanced immunity to the specific pathogen. The mechanism for the enhanced immunity remains to be fully determined; the relative importance of ex vivo expansion of PVC-specific memory T cells compared to the homeostatic in vivoexpansion following their infusion in lymphopenic patients is unclear. The cytokine milieu of the patient may be relevant to the in vivoexpansion and function of the infused T cells. Ultimately, the strategy developed by Rapoport et al. is exciting as it brings the goal of rebuilding immunity after cytotoxic therapy to the forefront and offers clues for designing studies using T cells and tumor vaccines to eradicate minimal residual disease after autologous HCT.
