Diana Cortés‐Selva

ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

In Escherichia coli, activity of the global regulatory RNA binding protein CsrA is antagonized by two non-coding sRNAs, CsrB and CsrC, which sequester it away from its lower affinity mRNA targets. Transcription of csrB/C requires the BarA-UvrY two component signal transduction system, which responds to short chain carboxylates. We show that two DEAD-box RNA helicases, DeaD and SrmB, activate csrB/C expression by different pathways. DeaD facilitates uvrY translation by counteracting the inhibitory effect of long distance base-pairing between the uvrY mRNA leader and coding region, while SrmB does not affect UvrY or UvrY-phosphate levels. Contrary to the prevailing notion that these helicases act primarily at low temperatures, DeaD and SrmB activated csrB expression over a wide temperature range. High-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) revealed in vivo interactions of DeaD with 39 mRNAs, including those of uvrY and 9 other regulatory genes. Studies on the expression of several of the identified genes revealed regulatory effects of DeaD in all cases and diverse temperature response patterns. Our findings uncover an expanded regulatory role for DeaD, which is mediated through novel mRNA targets, important global regulators and under physiological conditions that were considered to be incompatible with its function.

ABSTRACT: Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098.

Introduction: Teclistamab is an off-the-shelf, B-cell maturation antigen (BCMA) bispecific IgG4 antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. The multicohort, open-label, phase 1/2 MajesTEC-1 study is investigating safety/efficacy of teclistamab in patients with relapsed/refractory multiple myeloma (RRMM) who previously received ≥3 lines of therapy. In phase 1, the recommended phase 2 dose (RP2D) of teclistamab was identified as a weekly subcutaneous (SC) dose of 1.5 mg/kg preceded by step-up doses of 0.06 and 0.3 mg/kg. Initial results from patients treated at the RP2D in phase 1/2 (no prior exposure to a BCMA-targeted treatment) demonstrated that teclistamab was well tolerated, with encouraging efficacy. Here, we report translational research data from the pivotal RP2D and active dose cohorts of patients in the MajesTEC-1 study. Methods: Baseline or on-treatment whole blood and bone marrow aspirate samples from pivotal RP2D patients (SC) were analyzed by flow cytometry for BCMA expression or immune populations. Serum samples were analyzed for soluble BCMA (sBCMA) using an electrochemiluminescence ligand binding assay and for cytokines using MSD or Luminex assays. Whole blood from active dose cohorts (intravenous/SC) was analyzed by cytometry by time of flight (CyTOF). Results: Analysis of pivotal RP2D patients demonstrated that the baseline expression of BCMA on bone marrow plasma cells was prevalent and highly variable among patients with RRMM but was not associated with clinical responses to teclistamab. Higher sBCMA levels at baseline were associated with lower response rates and high-risk disease characteristics (higher revised International Staging System stage, high bone marrow plasma cells [>60%], and presence of extramedullary plasmacytoma). Nonresponding patients had lower peripheral CD8 T-cell counts, higher frequency of regulatory T cells (Tregs) and CD38+ Tregs, and higher overall frequencies of T cells that express markers, such as PD-1, TIM-3, and CD38, in both peripheral blood and bone marrow at baseline. Additional analysis at baseline using CyTOF showed the enrichment of memory CD8 T cells expressing PD-1, LAG-3, TIM-3, CD38, and HLA-DR and a higher number of natural killer (NK) cells in nonresponders, as well as an enhancement of a naïve phenotype in T cells in responders. A higher frequency of baseline T cells expressing PD-1, TIM-3, CD38, CD25, as well as PD-1/TIM-3 and PD-1/CD38, was observed in the blood and bone marrow of patients with high bone marrow plasma cells (>60%) and those with high composite tumor score (based on plasmacytosis ≥80%, serum M-spike ≥5 g/dL, and serum free light chain ≥5000 mg/L). Worse progression-free survival (PFS) was associated with higher frequencies of peripheral PD-1+ CD8, CD38+ naïve CD8, CD38+ effector memory CD4, and Tregs at baseline. A higher frequency of baseline CD25+ CD4 and CD38+ CD4 T cells in bone marrow was also correlated with decreased PFS after adjusting for tumor burden. Such a T-cell profile associated with worse clinical outcome likely reflects a dysfunctional and exhausted T-cell phenotype. Consistent with this hypothesis, a lower induction of interferon-gamma and PD-1+ CD8, CD25+ CD4, and CD38+ CD4 T cells was observed with teclistamab treatment in nonresponding patients. Furthermore, teclistamab-mediated induction of peripheral PD-1+ and PD-1+ CD38+ CD8 T cells was lower in patients with high tumor burden. Finally, occurrence of cytokine release syndrome was associated with higher CD3 T-cell frequency and lower baseline sBCMA, TIM-3, and PD-1/TIM-3 expressing CD4 T cells in the periphery. Conclusions: Analysis of baseline correlatives for pivotal RP2D patients suggests an emerging profile for non-responders of unfavorable immune characteristics at baseline, including lower T-cell numbers; higher frequency of T cells at baseline expressing markers such as PD-1, TIM-3, and CD38; higher frequency of Tregs and CD38+ Tregs; and lower proportion of naïve T cells and more NK cells. These data support clinical combinations of teclistamab with agents such as daratumumab or checkpoint inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal