The game of cat and mouse between the therapy administered and cancer relapse has molded the design of new cancer therapeutic strategies. For multiple myeloma, a cancer of the plasma cells that reside in the bone marrow, the standard of care regimen includes stem cell transplantation followed by treatment with an immunomodulatory drug called lenalidomide. This strategy provides the patient with donor stem cells that can become non-cancerous plasma cells while also activating the immune response to recognize the cancerous plasma cells in the bone marrow and mediate cancer cell killing. Despite initial success, patients typically relapse which is characterized by the cancer cells escaping detection by the immune cells. One strategy aimed at limiting relapse is to boost the immune response by blocking factors that inhibit the immune response. Dr. Geoffrey Hill’s Lab at Fred Hutchinson Cancer Center in the newly formed Translational Science and Therapeutics Division, previously part of the Clinical Research Division, and others have described the association between myeloma relapse due to T cell exhaustion and the expression of an immune inhibitor, TIGIT. With this potential new target, the Hill lab conducted studies in a pre-clinical mouse model of myeloma and identified the synergistic effect of stimulating the immune system via lenalidomide treatment and restricting TIGIT, an inhibitor of immune signaling, to extend relapse-free survival of mice. These data were published recently in the Journal of Clinical Investigation.
In this study, the Hill lab first compared the levels of TIGIT on CD8+ T cells, a type of immune cell, for patients with myeloma undergoing stem cell transplantation and healthy individuals. The myeloma samples exhibited higher levels of TIGIT on activated CD8+ T cells as compared to the healthy control samples. Previously, only an association between myeloma burden and TIGIT presence had been observed. Therefore, these findings highlighted high TIGIT expression as a unique feature of CD8+ T cells from patients with myeloma. Due to the role of TIGIT to inhibit the immune response, these observations may indicate that blocking TIGIT activity could have positive outcomes on T cell dysfunction and myeloma relapse.
The researchers transitioned to their mouse model of myeloma and employed monoclonal antibodies that recognize the TIGIT on the cell surface and limit TIGIT activity to block the inhibitory effect of TIGIT on immune cell activation. Herein, they discovered that the antibody that bound tightly to TIGIT resulted in higher rates of relapse-free survival for the myeloma mice following stem cell transplantation. However, there were a few mice that did not respond to the inhibition of TIGIT, suggesting that only blocking TIGIT immune inhibition would not be sufficient to prevent relapse in all cases. To determine if blocking TIGIT would synergize with the standard-of-care drug, lenalidomide, that activates the immune response, the researchers conducted combination experiments in their mouse model of myeloma. For these studies the researchers transplanted fewer donor T cells into the recipient mice and tested the effect of these therapies alone or in combination. Strikingly, blocking TIGIT and activating the immune response using lenalidomide produced a synergistic effect to enhance the survival of these mice as compared to the single therapy conditions or control condition. These data demonstrate pre-clinical evidence in the myeloma mouse model that lenalidomide and TIGIT inhibition enhance relapse-free survival in mice.
The researchers were curious about how this combination therapy and stem cell transplantation regimen was able to enhance relapse-free survival in their pre-clinical model of myeloma. Since the T cell response is known to be essential for immune cell-mediated killing of cancerous plasma cells and T cell dysfunction is related to increased myeloma relapse, the researchers conducted RNA-sequencing analyses on both gene expression and the T cell receptor repertoire of CD8+ T cells. From these data the researchers observed an expansion of polyfunctional, activated CD8+ T cells in the combination treated mice as compared to single and control treated mice. Additionally, the gene expression data revealed that lenalidomide was a key driver in T cell memory establishment and TIGIT inhibition increased granzyme B and other markers of T cell activation. The combination therapy also resulted in a reduction in genes associated with T cell exhaustion. Therefore, these findings highlight that in addition to immune cell activation, immune cell-mediated killing of cancer cells is also enhanced due to reduced T cell exhaustion in the combination treated mice.
“Our preclinical work has identified a novel immunotherapy combination approach to treat multiple myeloma that involves leveraging a standard-of-care drug to improve response to immune checkpoint inhibition,” stated first author Dr. Simone Minnie. And excitingly, “this combination approach is now being tested in a clinical trial in patients with relapse myeloma across multiple centers, including here at Fred Hutch.” Extending from the pre-clinical data in mice, “one future direction would be to perform these immune correlate studies in patients,” continued Dr. Minnie. Additionally, “we would be interested in looking at immune cell phenotypes associated with response versus resistance to combination therapy in patients to help inform future immunotherapy combinations.”
The spotlighted research was funded by the National Cancer Institute of NIH.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Leona Holmberg, Scott Furlan, and Geoffrey Hill contributed to this work.
Minnie SA, Waltner OG, Ensbey KS, Olver SD, Collinge AD, Sester DP, Schmidt CR, Legg SR, Takahashi S, Nemychenkov NS, Sekiguchi T, Driessens G, Zhang P, Koyama M, Spencer A, Holmberg LA, Furlan SN, Varelias A, Hill GR. 2023. TIGIT inhibition and lenalidomide synergistically promote antimyeloma immune responses after stem cell transplantation in mice. J Clin Invest. 133(4):e157907.