Immune Whispering: Safely Harnessing the GVL Effect Using Vaccination

For many advanced hematologic malignancies, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only therapy that is potentially curative. The initial strategy of allo-HSCT for treatment of leukemia was aimed at complete elimination of malignant cells within the bone marrow (inevitably accompanied by eradication of normal marrow elements) by delivering myeloablative doses of radiation and chemotherapy. The ablated marrow would then be rescued by transplant of donor stem cells. Quickly (and surprisingly), however, investigators came to realize that an important component of the therapeutic efficacy of allo-HSCT was initiation of a robust and sustained anti-tumor effect mediated by the developing donor-derived immune system. Awareness of the importance of the graft-versus-tumor effect came in part from observations that treatment failure was greater if the source of donor stem cells was a syngeneic twin or if the donor sample was depleted of T cells ex vivo. Investigation into the mechanisms involved in the graft-versus-leukemia (GVL) effect has provided important insights into the basis of the power of cancer immunotherapy, and the notion of harnessing the curative potential of the immune system has fueled the field of tumor immunology for decades. A major challenge that has plagued the field is avoidance or minimization of the toxic effects of graft-versus-host disease (GVHD) while preserving the GVL effect. Although some would argue that success has been limited, investigators can point to the use of donor lymphocyte infusion, manipulation of T regulatory cells, and inhibition of suppression of anti-tumor T cells by antibodies that target CTLA-4 and PD-1 as examples of how insights gained from allo-HSCT and tumor immunology have been translated into clinically applicable treatment modalities. Also because of lessons learned from allo-HSCT about the untoward consequences of GVHD, interest has focused on development of treatment approaches that more directly target the tumor cell. Exciting examples of this strategy include development of both chimeric antigen receptor (CAR) T cells and bi-specific T-cell engager (BiTE) compounds.

In another example of a strategy that has arisen from the study of tumor immunology, Ute Burkhardt and colleagues in the laboratory of Catherine Wu from Dana-Farber Cancer Institute in Boston set out to safely and effectively harness the GVL effect. To drive expansion of leukemia-specific T cells and thereby induce GVL immunity, the team of investigators used a well-characterized bystander-cell vaccine strategy in which irradiated K562 cells that secrete large amounts of GM-CSF are co-injected with irradiated tumor cells obtained from the patient prior to allo-HSCT. This vaccine, injected half subcutaneously and half intradermally, delivers a broad range of antigens including patient-specific tumor targets to antigen-presenting cells within the context of a GM-CSF driven pro-inflammatory environment.¹  This strategy has previously been investigated in solid and liquid tumors, but despite inducing detectable anti-tumor immunity, the array of immunosuppressive strategies that exist within the tumor environment including those mediated by PD-1 and CTL4A thwarted investigators using this approach.

In the present studies, Burkhardt et al. focused on patients with chronic lymphocytic leukemia (CLL) in whom reduced-intensity conditioning (RIC) was used as the preparative regimen prior to allo-HSCT. The benefit of RIC is that the treatment is less toxic than standard ablative regimens, resulting in a favorable therapeutic index for patients that would otherwise be unsuitable for allo-HSCT. The major disadvantage of RIC is dependence upon GVL for the elimination of residual leukemia cells. Given the unpredictable nature of GVL and our inability to specifically promote it, disease relapse has become a primary cause of treatment failure in patients whose treatment regimen includes an RIC-preparative regimen.

In this prospective, phase I study, 18 patients with an 8/8 HLA-matched, related or unrelated donor received six vaccinations between days 30 and 45 post-transplant. The authors reported an increase in leukemia-specific immune responses in patients who received the vaccine as compared with unvaccinated patients. Moreover, in the plurality of cases, ex-vivo testing revealed that this T-cell-driven response was capable of differentiating between tumor cells and non-malignant host tissues. Overall, after a median follow-up of 2.9 years (range, 1-4 years), the progression-free survival of vaccinated subjects was 82 percent.