Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial

Schmitt, Michael; Hückelhoven, Angela; Hundemer, Michael; Schmitt, Anita; Lipp, Susanne; Emde, Martina; Salwender, Hans; Hänel, Mathias; Weisel, Katja; Bertsch, Uta; Dürig, Jan; Ho, Anthony D.; Blau, Igor Wolfgang; Goldschmidt, Hartmut; Seckinger, Anja; Hose, Dirk

doi:10.18632/oncotarget.11215

Cited by 6 publications

(7 citation statements)

References 60 publications

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“…HM1.24 is widely expressed in myeloma cells (45,46). However, NY-ESO-1 is known to be expressed in < 30% of multiple myeloma patients (45)(46)(47). Compared with this low positive rate for NY-ESO-1 expression in historic data, NY-ESO-1 157-165 -specific CD8 þ T cells were detected with a relatively high rate (20/29, 69.0%) in the present study.…”

Section: Aacrjournalsorgcontrasting

confidence: 54%

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PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

Kwon

Kim

Lee

et al. 2020

Clinical Cancer Research

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Purpose: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, antiprogrammed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.Experimental Design: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8 þ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGFb inhibitors.Results: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8 þ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8 þ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally dif-ferentiated phenotype. These results were also observed in BM CD8 þ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8 þ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8 þ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8 þ T cells from multiple myeloma patients in the presence of inhibitors of TGFb, which was overexpressed by myeloma cells.Conclusions: Our findings indicate that combined blockade of PD-1 and TGFb may be useful for the treatment of multiple myeloma.

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Section: Aacrjournalsorgcontrasting

confidence: 54%

“…First, the expression of myeloma antigens (NY-ESO-1 and HM1.24) in myeloma cells was not examined, although myeloma antigen-specific CD8 þ T cells were studied in multiple myeloma patients. HM1.24 is widely expressed in myeloma cells (45,46). However, NY-ESO-1 is known to be expressed in < 30% of multiple myeloma patients (45)(46)(47).…”

Section: Aacrjournalsorgmentioning

confidence: 99%

PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

Kwon

Kim

Lee

et al. 2020

Clinical Cancer Research

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“…RNA-sequencing was performed as published ( 12 , 16 , 17 ). In brief, full-length double-stranded cDNA was generated from 5 ng of total RNA and amplified using the SMARTer Ultra Low RNA Kit (Illumina, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

CD38 as Immunotherapeutic Target in Light Chain Amyloidosis and Multiple Myeloma—Association With Molecular Entities, Risk, Survival, and Mechanisms of Upfront Resistance

et al. 2018

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Monoclonal antibodies against the cell surface antigen CD38, e.g., isatuximab, daratumumab, or Mor202, have entered the therapeutic armamentarium in multiple myeloma due to single agent overall response rates of 29 vs. 36 vs. 31%, effectivity in combination regimen, e.g., with lenalidomide or bortezomib plus dexamethasone, and tolerable side effects. Despite clinical use, many questions remain. In this manuscript, we address three of these: first, upfront CD38 target-expression in AL-amyloidosis, monoclonal gammopathy of unknown significance (MGUS), asymptomatic, symptomatic, and relapsed multiple myeloma. Second, relation of CD38-expression to survival, disease stages, molecular entities, and high-risk definitions. Third, alternative splicing or lack of CD38-expression as potential mechanisms of upfront resistance. We assessed CD138-purified plasma cell samples from 196 AL-amyloidosis, 62 MGUS, 259 asymptomatic, 764 symptomatic, and 90 relapsed myeloma patients, including longitudinal pairs of asymptomatic/symptomatic (n = 34) and symptomatic/relapsed myeloma (n = 57) regarding interphase fluorescence in situ hybridization (n = 1,380), CD38-expression by gene expression profiling (n = 1,371), RNA-sequencing (n = 593), and flow cytometry (n = 800). Samples of normal bone marrow plasma cells (n = 10), memory B-cells (n = 9), polyclonal plasmablastic cells (n = 9), and human myeloma cell lines (n = 54) were used as comparators. CD38 was expressed in all malignant plasma cell samples, but significantly lower compared to normal plasma cells with small but significant downregulation in longitudinal sample pairs. Higher CD38 expression was associated with the presence of t(4;14) and high-risk according to the UAMS70-gene score, lower expression was associated with del17p13 and hyperdiploidy in symptomatic myeloma as well as t(11;14) in asymptomatic myeloma. Higher CD38-expression was associated with slower progression to symptomatic and relapsed myeloma and better overall survival in the latter two entities. CD38 expression, t(4;14), del17p13, and gain of 1q21 are independently prognostic in multivariate analysis. By contrast, high CD38-expression is associated with adverse survival in AL-amyloidosis. Regarding mechanisms of upfront anti-CD38-treatment resistance, lack of CD38-expression and alternative splicing of receptor binding-sites could be excluded. Here, of the two protein coding CD38-transcripts CD38-001 (eight-exon, full length) and CD38-005 (truncated), CD38-001 conveyed >97% of reads spanning the respective CD38 splice junction.

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“…Then, we validated novel RNA therapeutics targeting these regions. Targeting HMMR has been previously evaluated with HMMR peptide vaccination in MM and other malignancies [37][38][39]. Although HMMR peptidespecific immune responses were induced, clinical outcomes were mixed [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics

et al. 2023

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Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM patients demonstrated that alterations in pre-mRNA splicing (AS) are frequent in MM. This manuscript describes approaches to identify disease-specific alterations in MM and proposes RNA-based therapeutic strategies to eradicate such alterations. As a “proof of concept”, we examined the causes of aberrant HMMR (Hyaluronan-mediated motility receptor) splicing in MM. We identified clusters of single nucleotide variations (SNVs) in the HMMR transcript where the altered splicing took place. Using bioinformatics tools, we predicted SNVs and splicing factors that potentially contribute to aberrant HMMR splicing. Based on bioinformatic analyses and validation studies, we provided the rationale for RNA-based therapeutic strategies to selectively inhibit altered HMMR splicing in MM. Since splicing is a hallmark of many cancers, strategies described herein for target identification and the design of RNA-based therapeutics that inhibit gene splicing can be applied not only to other genes in MM but also more broadly to other hematological malignancies and solid tumors as well.

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Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial

Cited by 6 publications

References 60 publications

PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

CD38 as Immunotherapeutic Target in Light Chain Amyloidosis and Multiple Myeloma—Association With Molecular Entities, Risk, Survival, and Mechanisms of Upfront Resistance

Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics

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