Patients inflicted with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia, are often unable to effectively replenish the body’s demand for hematopoietic stem cells. These cells are primarily responsible for the constant renewal of blood, which provides constant maintenance and immune protection of the human body, and the production of various specialized cells, like macrophages, platelets, and T-cells. To restore these stem cells, hematopoietic stem cell transplants have become useful treatment options. Unlike autologous transplants, in which patients receive their own stem cells, allogeneic transplants involve the transfer of stem cells from an individual donor (usually a sibling).

Due to certain trigger factors, those receiving transplants with stem cells from an unrelated person are often predisposed to the reactivation of viruses, such as herpes and cytomegalovirus. Although several drugs have been effective in treating these symptoms, it is limited by side effects and the development of resistance to the drugs. As a result, the transfer of the donor’s T cells to the transplant recipient may be considered as an alternative therapeutic strategy.

In order to test the best method to transplant T-cells, scientists performed a series of experiments to study how T-cells respond to a foreign substance such as the transplanted cells from an unrelated donor.

Memory T-cells are the cells that remember to respond to a foreign antigen that the body saw a long time before, such as vaccines. The memory T-cells reside in the blood for the live of the individual so they are poised to combat future infections by responding to clear the infection. This unique functionality allowed scientists to initially isolate a group of T-cells from mice that were exposed to bacteria. These T-cells were then injected into another group of mice that were deficient in immune cells. The results showed approximately 1-100 T-cells were able to provide protection against the bacteria in the transplanted mice.

This observation encouraged scientists to shift their focus to a specific population of T-cells within the blood. In comparison to the previously established notion that more specialized, older T-cells gave rise to younger ones during expansion, their findings illustrated the exact opposite - younger primitive T-cells gave rise to the older ones and persisted in the body to combat infection. To be specific, there seems to be an unusual ability of the memory T-cells to be protected similar to stem cells. As needed, the primitive T-cells then form older responding T-cells.

This advantage allowed scientists to extend their mouse work to patients who received allogeneic transplants and suffered from the reactivation of cytomegalovirus. Using a small dose of the same population of T-cells, they found a similar, robust T-cell expansion within these patients, enabling them to successfully fight a recurrent infection.

Transplantation of hematopoietic stem cells is a standard treatment of various hematological diseases. However, the procedure has a relatively high rate of severe, possibly lethal complications. This study indicated that the transfer of a small subset of T-cells can be a successful strategy for protecting the human body from infections several months after receiving allogeneic transplants.

SCIENTIFIC REVIEW

Patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) suffer from the side effects associated with lymphocyte-depleting conditioning regimens. Consequently, reactivation of highly prevalent endogenous herpes viruses, such as herpes simplex virus and Epstein-Barr virus, and cytomegalovirus occurs. Although prophylactic or preemptive virostatic treatment with ganciclovir or foscarnet is effective, its success is limited by side effects and resistance development. As a result, adoptive transfer of virus-specific memory T cells derived from the stem cell donor has been proposed as an alternative therapeutic strategy.

To establish a lower limit for successful adoptive T-cell therapy, investigators conducted low-dose antigen specific T-cell transfers in a murine infection model with the intracellular bacterium Listeria monocytogenes (L.m). B6 wt mice were initially challenged with L.m.-Ova infection to isolate ova-peptide-specific T cells, which enhance the proliferation of highly diversified T-cell populations. To test whether these developing T-cells would be sufficient to protect against infection, T- and B-cell-devoid RAG-/- recipient mice were infected with L.m.-Ova. In the presence and absence of a MVA-Ova boost vaccination, very low numbers of adoptively transferred L.m.-specific CD8+ T cells proliferated and differentiated functionally, conferring protection against high-dose bacterial infection.

Since naïve antigen-specific precursor T cells are often very low in frequency within human blood, investigators expanded their focus to circulating antigen-experienced T cells. Since both CD62Lhi and CD62Llo memory T cells contribute to protection against reinfections with L.m. in mice, their survival and differentiation potential were examined. The lowest numbers of CD62Lhi memory T cells developed into diversified progenies, identifying this subpopulation as the most effective for adoptive immunotherapy. Thus, this finding of CD62Lhi memory T cells being more potent than more differentiated CD62Llo memory T cells coincides with the linear model of T-cell differentiation. Unlike previous models, this model proposes that less differentiated memory cells give rise to effector cells.

To realistically mimic a potential source of CD62Lhi memory T cells for future adoptive T-cell transfers in humans, single memory T cells derived from polyclonal Ova-peptide-specific CD62Lhi CD8+ T cells using MHC Streptamers were performed. Taken together, both naïve and antigen-experienced CD62Lhi memory T cells were successfully able to expand, differentiate, and confer protection against L.m. infection.

Finally, the reconstitution capacity of human low-dose T cell transfers was demonstrated by the expansion of Streptamer-enriched CMV-specific CD8+ T cells in 2 allo-HSCT patients. These two clinical cases showed strong pathogen-specific T-cell expansion and differentiation in immunocompromised patients.

Although HSCT has become the standard treatment of various hematopoietic malignancies, it bears a high rate of severe, possibly lethal, complications. As a result, low-dose adoptive T-cell transfer could be a successful strategy for restoring antiviral immunity and alleviating the first months of high susceptibility after allo-HSCT, especially with the use of less differentiated memory cell subgroups.