Multiple myeloma (MM) is a condition in which cancerous plasma cells that overwhelm the bone marrow. Chemotherapy followed by autologous stem cell therapy (ASCT) is a current treatment for patients with MM. ASCT is primarily a means of delivering very high dose chemotherapy, effectively reducing the number of myeloma cells. However, some myeloma cells survive after ASCT and repopulate the bone marrow, resulting in eventual disease progression.
In a study published in the Journal of Clinical Investigation, the laboratory of Dr. Geoffrey Hill (Clinical Research Division) at Fred Hutch, and his group at QIMR Berghofer Medical Research Institute in Brisbane, utilized a preclinical model of MM (Vk*MYC mice) that allowed them to study the mechanisms of action of ASCT. Dr. Hill and colleagues used Vk*MYC myeloma cells to generate MM in mice and then administered myeloablative doses of total body irradiation, followed by ASCT, thereby reducing myeloma cells and lymphocytes and resulting in inflammation similarly to what is observed in patients. They transplanted stem cell grafts using T cell-depleted bone marrow (TCD-BMT), bone marrow replete with naïve T cells (BMT), or bone marrow replete with T cells from mice which had previously experienced Vk*MYC myeloma (BMT+). Dr. Hill and colleagues found that a fraction of mice in both BMT and BMT+ groups had long-term myeloma control and survival. In contrast, myeloma progressed in all the TCD-BMT recipients.
Image by Madeleine Kersting Flynn, QIMR Berghofer
Knowing that T cells contributed to myeloma control in this model, Dr. Hill next investigated whether this contribution was mainly from memory or naive T cells. To solve this, the team isolated memory T cells from myeloma experienced donors using CD44 as a selection marker. They then repeated the transplants with either CD44+ memory or CD44- naive T cells in the stem cell graft. Whereas treatment with BM+ CD44- T cells had a significant but modest impact, transfer of BM+ CD44+ T cells dramatically increased survival of the mice.
Upon examining the cell types in the bone marrow of these mice after transplant, the researchers noticed mice transplanted with CD44+ cells had higher numbers of effector/memory CD8+ cells, some of which were exhausted, when compared to the CD44- transplanted group.
Intrigued by this increase in CD8 memory T cells, the scientists decided to test whether these were indeed the key to controlling myeloma in this model. They isolated CD4+ or CD8+ T cells from mice with long-term control of myeloma and transferred them into newly transplanted mice with myeloma. The mice which received CD8+ cells from MM experienced mice controlled the myeloma, while recipients of MM experienced CD4+ cells did not. This suggests that autologous grafts containing myeloma-specific memory CD8+ T cells could be the key to controlling MM.
In order to improve responses to myeloma after ASCT, the scientists tested an agonistic antibody against a costimulatory molecule CD137, which is expressed on activated T cells among others. They administered the CD137 agonist to mice after BMT, which greatly improved survival and eliminated myeloma from BM. They also noticed an increase in activated T cells secreting interferon gamma in the BM, some of which were becoming exhausted. To prevent this exhaustion, the scientists tested concurrent therapy with an anti-PD-1 blocking antibody and a CD137 agonist, which further improved the anti-myeloma effect.
This study comes at an exciting time, as there are currently FDA approved anti-PD-1 immunotherapies (Keytruda and Opdivo) as well as ongoing clinical trials of CD137 agonists for treating cancer. “This study suggests that autologous stem cell transplantation is the ideal platform for subsequent immunotherapy of multiple myeloma,” Dr. Hill said.
Vuckovic S, Minnie SA, Smith D, Gartlan KH, Watkins TS, Markey KA, Mukhopadhyay P, Guillerey C, Kuns RD, Locke KR, Pritchard AL, Johansson PA, Varelias A, Zhang P, Huntington ND, Waddell N, Chesi M, Miles JJ, Smyth MJ, Hill GR. 2019. Bone marrow transplantation generates T cell–dependent control of myeloma in mice. The Journal of Clinical Investigation.129(1):106-21.
Funding for this research was provided by the Cancer Council Queensland and the National Health and Medical Research Council
Fred Hutch/UW Cancer Consortium member Geoffrey Hill led this research.