Finding curative treatments for cancer or other diseases can often be a case of moving two steps forward and one step back, where beneficial treatments can improve outcomes, but create an additional problem to solve. Bone marrow transplants (BMT) have been transformative in treating blood cancers by replacing diseased blood stem cells with healthy ones. An added benefit of BMT is that transplanted donor immune cells are often able to aid in fighting off cancerous cells. Unfortunately, not all cancers respond well to these donated immune cells. In responsive blood cancers such as leukemia, donor (or graft) T cells efficiently attack tumor cells, known as an effective “graft-versus-tumor” response. In contrast, cancers like myeloma are inherently resistant to this therapy. So, what makes blood cancer cells susceptible to donor immune cell detection and killing? This is the question investigated by researchers in the lab of Dr. Geoffrey Hill, Professor in the Clinical Research Division and Director of Hematopoietic Stem Cell Transplantation and the Immunotherapy Integrated Research Center at Fred Hutch. In their recent Science Immunology study led by postdoctoral fellow Dr. Simone Minnie, the researchers discovered that this resistance in myeloma was driven by donor T cells becoming functionally exhausted from exposure to foreign antigens on recipient cells, rather than from fighting tumor cells. When Minnie figured out how to solve this T cell exhaustion problem, she ran into a new one- the remaining T cells left behind were not in an activated tumor-fighting state. Through creative approaches, the Hill researchers found an innovative way to activate these T cells and developed a potential therapeutic approach to tackle these difficult to treat blood cancers.
To figure out what makes some cancers unresponsive to the beneficial graft-versus-tumor response following bone marrow transplantation, Dr. Minnie developed preclinical models that were responsive (leukemia) and ones that were resistant (myeloma). The researchers predicted that one reason for this treatment response difference might be that myeloma causes donor T cell exhaustion, which can occur if T cells aren’t able to fight off a cancer fast enough and become functionally exhausted and less efficient at killing malignant cells. The authors profiled T cells several weeks following bone marrow transplantation from healthy donor mice (known as an allogeneic bone marrow transplant). In the absence of cancer, transplanted T cells were exposed to unfamiliar host antigens, or alloantigens, that “drove an exhausted T cell phenotype, characterized by high expression of inhibitory receptors on CD8+ T cells,” Minnie explains. Excitingly, they found that myeloma “tumors that were resistant to graft-versus-tumor effects expressed high levels of complimentary inhibitory ligands,” compared to leukemia cells. This indicated that myeloma cells selectively expressed proteins that might be able to quench the tumor-fighting ability of the T cells and promote immune escape. However, when they tried to block this inhibitory action of the myeloma cells, the researchers found this was still not sufficient to induce graft-versus-tumor responses in myeloma mouse models.
Minnie et al. next asked if they could instead deplete the exhausted, alloreactive T cells and see if the remaining donor T cell subsets could promote graft-versus-tumor responses. To do so, they treated mice with cyclophosphamide (PT-Cy), a cytotoxic drug given to transplant patients to prevent graft-versus-host-disease, which occurs when donor immune cells attack the host’s healthy cells in addition to diseased ones. PT-Cy works by strongly attenuating alloreactive T cell responses. Dr. Minnie explains that “the subset of T cells that were spared by PT-Cy are stem-like memory T cells,” which were not yet in an activated state and not very useful at fighting off myeloma cells. Minnie adds that “these cells express the [IL-18 receptor] IL-18R in human bone marrow after allogeneic stem cell transplantation,” in addition to expressing IL-18R in their mouse model. The authors then sought to activate this remaining T cell population with a synthetic cytokine that promotes T cell-mediated anti-tumor responses and is resistant to IL-18 inhibitors produced by myeloma cells. When administered after PT-Cy, the synthetic cytokine decoy-resistant IL-18 promoted anti-myeloma responses without generating graft vs. host disease- one of the main risks with any type of immune targeting-treatment. The authors went on to show that decoy-resistant IL-18 promotes potent graft-versus-tumor effects by reducing CD8+ T cell exhaustion and expanding cytotoxic natural killer cells.
Collectively, the authors uncovered “novel mechanisms of graft-versus-tumor resistance and highlighted a therapeutic strategy that improves graft-versus-tumor responses, even in already sensitive leukemia models,” Dr. Minnie states. Importantly, the drug responsible for this improvement in graft-versus-tumor response, decoy-resistant IL-18, “is already in clinical trials for solid tumors. Therefore, this is a clinically attractive intervention that we hope to see translated to hematological malignancies.” The authors are focusing on moving this work from the lab into the clinic in addition to “exploring additional mechanisms of action of IL-18 signaling, particularly in natural killer cells, after PT-Cy.” Dr. Minnie acknowledges “Scott Furlan’s lab at the Fred Hutch who performed all the bioinformatics analyses, Aaron Ring’s lab from Yale who provided the decoy-resistant IL-18, and Michael Boeckh also at Fred Hutch who provided clinical samples.”
This work was funded by the National Cancer Institute, the American Society for Transplantation and Cellular Therapy and the Klorfine Foundation.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Geoffrey Hill, Scott Furlan, Michael Boeckh and Kate Markey contributed to this work.
Minnie SA, Waltner OG, Ensbey KS, Nemychenkov NS, Schmidt CR, Bhise SS, Legg SRW, Campoy G, Samson LD, Kuns RD, Zhou T, Huck JD, Vuckovic S, Zamora D, Yeh A, Spencer A, Koyama M, Markey KA, Lane SW, Boeckh M, Ring AM, Furlan SN, Hill GR. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity. Sci Immunol. 2022 Oct 21;7(76):eabo3420. doi: 10.1126/sciimmunol.abo3420. Epub 2022 Oct 14. PMID: 36240285.