In patients with multiple myeloma (MM) undergoing bispecific T-cell engager (TCE) therapy, treatment response was determined by the expansion of certain pre-existing T-cell clones. This is according to a study published in Cancer Cell, which also found that the induction of major histocompatibility complex (MHC) class I in tumor cells could be of therapeutic benefit.
“Treatment with bispecific antibodies is already approved for relapsed or refractory [MM]. Unfortunately, however, the treatment does not work equally well in all patients,” explained lead author Micro J. Friedrich, MD, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. “We discovered that the effect of bispecific antibodies does not depend on classical clinical characteristics, such as age, secondary diseases, or previous therapies, but very much on the patient’s own immune repertoire and its ‘immune fitness,’ in particular the amount of activatable CD8-positive T cells.”
The translational study by Dr. Friedrich and colleagues examined the effect of TCEs on patients with MM. The researchers used an MM model to perform a longitudinal interrogation of T cells in patients’ peripheral blood and bone marrow, as well as to analyze expanded T-cell receptor (TCR) clonotypes. Of 30 patients, five were healthy bone marrow donors, seven were newly diagnosed with MM, and 18 had relapsed or refractory MM and were receiving BCMA×CD3 bispecific antibody monotherapy. Publicly available healthy bone marrow and newly diagnosed MM single‐cell RNA sequencing datasets were integrated into the final dataset. Longitudinal bone marrow biopsies and peripheral blood draws were performed on patients receiving TCE therapy, enabling analyses of the immune repertoire during therapy.
Clinical practice cannot differentiate patients who may benefit from therapy with bispecific antibodies versus those who may not respond or could develop resistance, Dr. Friedrich noted. He and his colleagues developed an analysis method to predict potential responses “based on a patient’s individual T-cell landscape,” he said.
“By looking at the activity status of T cells, patients who are very likely to benefit from therapy can be more easily identified,” Dr. Friedrich explained. “On the other hand, for patients in whom the form of therapy is unlikely to work well, another option can be sought more quickly. Thus, not only could therapy costs be saved, but these patients could be spared side effects and potentially given additional (life) time.”
Single-cell TCR tracing successfully identified conserved T-cell responses to TCEs. The data showed that TCE response in MM was determined by the clonal expansion of certain pre-existing T-cell clones. Specifically, clonal expansion of effector CD8+ T cells was shown to be an immunologic driver of TCE therapy, while the abundance of exhausted CD8+ clones was associated with response failure in MM. Moreover, activation of CD8+ T cells by TCEs was amplified by MHC class I:TCR co-signaling.
“We show that naïve CD8+ T-cell clones represent an alternative route of TCE-induced immune response. These cells can be further stimulated by allowing MHC class I:TCR interactions,” the authors wrote. This suggests that inducing MHC class I in tumor cells – for example, in irradiated extramedullary disease – may be beneficial.
“These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies,” they concluded.
A limitation of this study was the limited number of T cells with each sampling and the corresponding binomial sampling uncertainty.
Any conflicts of interest declared by the authors can be found in the original article.
Friedrich MJ, Neri P, Kehl N, et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients [published online ahead of print, 2023 Mar 9]. Cancer Cell. doi: doi.org/10.1016/j.ccell.2023.02.008.