GPRC5D expression

Moreover, G protein-coupled receptor class C Group 5 member D (GPRC5D) is highly expressed in MM cells independently of B cell maturation antigen (BCMA) and is a highly promising target following BCMA. Aside from emphasizing the therapeutic efficacy and safety of targeting GPRC5D for the treatment of MM, this study also provides a prospective view on the mechanisms of drug resistance and relapse associated with GPRC5D-targeted therapies, as well as the timing of sequential or combined treatment strategies involving the dual targeting of both GPRC5D and BCMA.

Compared with blank control group and negative control group, the siGPRC5D-AS1 group showed a significant decrease in the relative expression of lncRNA GPRC5D-AS1 (P<0.05), a significant increase in the number of proliferating cells and migrating cells (P<0.05), a significant increase in the tumor volume of nude mice (P<0.05), a significant increase in β-catenin, Ki67, PCNA and N-cadherin protein expression (P<0.05), and a significant decrease in E-cadherin protein expression (P<0.05); conversely, these results were opposite for the eGPRC5D-AS1 group. Silencing the expression of lncRNA GPRC5D-AS1 can enhance the proliferation, invasion, and migration ability of renal cancer cell line 786-0, which can be weakened by the overexpression of lncRNA GPRC5D-AS1.

BsAb5003 also demonstrated significant inhibition of in vivo tumor growth by recruiting T cells. Taken together, these results suggest that T cell-redirecting bispecific antibody targeting GPRC5D as monotherapy and combination therapy with IMiDs could be a highly potent and effective treatment approach for a wide population of MM patients.

Meanwhile, antitumor activity was demonstrated in MM cell line xenograft mouse models with human immune cell reconstitution. These preclinical studies have formed a solid foundation for the evaluation of MM treatment efficacy in clinical trials.

P1, N=0, Withdrawn, The First Affiliated Hospital of Soochow University | N=30 --> 0 | Trial completion date: Dec 2025 --> Oct 2023 | Not yet recruiting --> Withdrawn | Trial primary completion date: Dec 2025 --> Oct 2023

GPRC5D-targeting DNA vaccines are a cost-effective prevention agent for MGUS and smoldering myeloma.

Neurotoxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurs mainly after CRS resolution and it should be managed with antiepileptics or antipsychotic and high-dose corticosteroids; tocilizumab (in case of concomitant CRS) or anakinra (anti IL-1) can be needed in refractory cases.2 Furthermore, some patients might develop late Parkinson’s disease-like movement disorders as reported in CARTITUDE-1 trial.3 Macrophage activated syndrome (MAS) is rare but potentially life-threatening condition; corticosteroids, tocilizumab and anakinra are crucial for event control.2 Both BsAbs and CAR-T are associated to a high risk of infection or viral reactivation because of neutropenia, lymphopenia and hypogammaglobulinemia. Periodically granulocyte colony-stimulating factor (G-CSF) could be useful in patients with G ≥3 neutropenia, although it may be ineffective due to underlying pathogenesis (e.g. low bone marrow reserve rather than inflammation)4 . Prophylactic administration of immunoglobulin is recommended in patients with hypogammaglobulinemia (<400 mg/dL) or recurrent bacterial infections.4 Antiviral or antibacterial prophylaxis should be considered as well.4 Efforts to enhance patients’ protection with vaccination seem pointless until lymphopenia recovery.5 Off-target anti-GPRC5D effects related to the presence of GPRC5D on keratin-expressing cells include skin or nail changes and dysgeusia reported mostly after BsAbs administration,6 while cerebellar neurotoxicity was solely noted after anti-GPRC5D CAR-T infusion.7

More than 97% of CAR inserted-iPSCs (CAR-iPSCs) expressed anti-GPRC5D scFV with a similar expression level identified in CAR-iPSC-derived-NK cells (CAR-iNK, 92.7%). The anti-GPRC5D CAR-iNK demonstrated high purity (>99.9% for CD45+ and CD56+

Our hybrid bispecific TCR/CAR also demonstrated superior anti-tumor efficacy compared to a previously described, and systematically optimized bispecific CAR format (Zah et al., 2020). Bispecific hybrid T cell receptors embedded with natural TCR signaling machinery represent a promising therapeutic option to address antigen downmodulation/loss and antigen heterogeneity for treatment of cancer.

Our study provides hint evidence that LPAR1 and LPAR5 increase the MM cell-surface expression of GPRC5D and improve the efficacy of anti-GPRC5D CAR T-cell therapy, which might be as novel GPCR partners of GPRC5D for the efficient CAR-T therapy of multiple myeloma.

To evaluate if cereblon modulation represents a strategy to improve PFS, we combined fixed-duration forimtamig with either pomalidomide (pom) or iberdomide (iber) at C1 day 1 (C1D1). Taken together, our data suggest that combination with CELMoDs but not IMIDs can prevent relapse to forimtamig driven by GPRC5D negative tumor cells. We confirm timing of intervention with CELMoDs to have an significant impact on PFS and cytokine release and suggest a broad therapeutic window using low dose forimtamig and intermittent dosing of iberdomide or mezigdomide.

JNJ-79635322 is a potential first-in-class trispecific antibody targeting BCMA and GPRC5D with the ability to deplete dual and single target expressing MM clones in preclinical studies vitro and in vivo. A Phase 1 dose-escalating study of JNJ-79635322 in myeloma patients is ongoing (NCT05652335).

Background: Dysgeusia is a common, yet underexamined side-effect of anti-tumor therapy. Our results demonstrate the importance of monitoring taste perception and quality of life changes caused by cancer therapies. The frequency of dysgeusia is underreported in MM patients receiving BCMA bispecifics and melphalan therapy. For optimal nutritional management, hospitals should consider patients' individual taste preferences.

GPRC5D, FcRH5 and BCMA are highly prevalent across MM patient subgroups, including high-risk patients who may warrant targeted therapy approaches. Based on our data and previously published work for FcRH5- and BCMA-targeted T-cell bispecifics (Sumiyoshi et al. EHA 2021; Cortes-Selva et al.

Our findings highlight that the baseline BM immune repertoire and the PB immune changes during Tal treatment may predict long term outcomes. Further in vitro mechanistic studies of T cell function and fitness and validation of these results in independent cohorts will be critical to develop these into predictive biomarkers of long-term response to Tal.

Introduction: Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody (BsAb), has shown deep and durable responses with overall response rates (ORRs) >71%, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (MM) in the MonumenTAL-1 study (NCT03399799/NCT04634552). Baseline immune profiling in heavily pretreated pts from MonumenTAL-1 suggested that compared to pts with prior TCR, pts with no prior TCR had a favorable immune fitness profile (less T-cell dysfunction and immune suppression). In both cohorts, baseline and longitudinal correlative analyses suggest a mechanism of resistance for nonresponders including lower T-cell counts and higher frequency of Tregs and expression of coinhibitory markers on CD8+ T cells, whereas responders show greater T-cell activation and recovery of CD3+ T cells that was sustained longitudinally. Progression data indicated an exhausted T-cell phenotype for pts who relapsed on tal.

Our patients with heavily pretreated multiple myeloma may harbor greater tumor heterogeneity and genomic instability than previously described, which can facilitate clonal outgrowth of antigen-negative tumor cells under continuous selective pressure of GPRCRD-targeted CAR T cells. Potential strategies to mitigate antigen escape-mediated relapse in myeloma patients receiving T-cell engaging therapies including earlier use of these therapies, multi-antigen targeting, or combination approaches are being evaluated in ongoing trials.

Refractoriness to specific drugs was observed, such as bortezomib (49%), carfilzomib (27%), lenalidomide (49%), pomalidomide (33%), daratumumab (49). By incorporating critical information on drug resistance patterns and expression of key targets like GPRC5D, TNFRSF17 (BCMA) and FcRH5, we enable precision medicine approaches for improved management of relapsed refractory myeloma. These findings open avenues for tailored and more effective therapeutic strategies, promising better outcomes for patients with relapsed refractory myeloma.

P1, N=12, Recruiting, Nanjing IASO Biotechnology Co., Ltd. | Not yet recruiting --> Recruiting