Dataset Information

Discovery and Development of CD70 As a Cellular Therapy Target in High Risk Multiple Myeloma

ABSTRACT: Even in the BCMA CAR-T era, multiple myeloma (MM) patients with high-risk genotypes have the poorest outcomes. We thus leveraged MMRF CoMMpass data to identify potential novel surface immunotherapeutic targets in high-risk MM. As described below, we focused on CD70, an immunotherapeutic target known to be upregulated on many hematologic and solid tumors but minimally expressed on normal tissue. While CD70 was previously explored in MM (McEarchern et al, Clin Cancer Res (2008)), it was not further investigated due to heterogeneous expression in newly diagnosed samples. Here we revisit this target to suggest cellular therapies against CD70 could be highly beneficial in high-risk MM patients, currently the greatest unmet need in the field.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Arun Wiita

LAB HEAD: Arun Wiita

PROVIDER: PXD048492 | Pride | 2025-11-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	231118_MV4_11_R1_Slot2-26_1_806.mzML	Mzml
	231118_MV4_11_R2_Slot2-30_1_811.mzML	Mzml
	231118_THP1_R1_Slot2-27_1_807.mzML	Mzml
	231118_THP1_R2_Slot2-28_1_809.mzML	Mzml
	231120_AMO1_R1_Slot2-19_1_768.mzML	Mzml

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Publications

Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR T cells.

Kasap Corynn C Izgutdina Adila A Patiño-Escobar Bonell B Kang Amrik S AS Chilakapati Nikhil N Akagi Naomi N Manoj Ananya A Johnson Haley H Rashid Tasfia T Werner Juwita J Barpanda Abhilash A Geng Huimin H Lin Yu-Hsiu T YT Rampersaud Sham S Gil-Alós Daniel D Sobh Amin A Dupéré-Richer Daphné D Aleman Adolfo A Wicaksono Gianina G Kelii K M Kawehi KMK Dalal Radhika R Ramos Emilio E Vijayanarayanan Anjanaa A Lakhani Kiran K Salangsang Fernando F Phojanakong Paul P Camara Serrano Juan Antonio JA Zakraoui Ons O Tariq Isa I Chari Ajai A Chung Alfred A Kumar Anupama D AD Martin Thomas G TG Wolf Jeffrey J Wong Sandy W SW Steri Veronica V Shanmugam Mala M Boise Lawrence H LH Kortemme Tanja T Parekh Samir S Stieglitz Elliot E Licht Jonathan D JD Karlon William J WJ Barwick Benjamin G BG Wiita Arun P AP

Blood 20250801 7

<h4>Abstract</h4>Despite the success of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells (CAR-Ts) in multiple myeloma, patients with high-risk cytogenetic features continue to relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high-risk myeloma tumors. We use a structure-guided design to ...[more]

PMID: 40359480

Similar Datasets

Project description:Multiple myeloma (MM) immune escape resulting from B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates MM resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging clinical data also suggests that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D), another promising target antigen expressed on MM cells, is observed in patients at relapse post anti-GPRC5D CAR T, but the genomic mechanisms that underlie GPRC5D loss has not been described. In order to examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk whole genome sequencing and single cell copy number variation analysis on CD138+ cells from bone marrow aspirates of patients before and after relapse from anti-BCMA or -GPRC5D CAR T/ TCE. We describe five cases with distinct biallelic events on TNFRSF17 at MM relapse after CAR T/ TCE. In addition to focal biallelic deletions at the TNFRSF17 locus acquired at relapse, BCMA negative clones can emerge from the selective expansion of subclones with homozygous TNFRSF17 loss that exist prior to any anti-BCMA therapy exposure. Furthermore, we corroborate with functional data to demonstrate that three different non-truncating mutations in the extracellular domain of BCMA negates the efficacies of BCMA directed TCEs and mediate disease relapse in patients. With respect to GPRC5D, we report four cases of MM relapse with biallelic loss of GPRC5D following anti-GPRC5DxCD3ε. Our data support that immunoselection of BCMA negative or mutant clones post anti-BCMA therapies may be more frequent than currently accepted in the field, and that an all or none screening approach for BCMA expression is inadequate to detect pertinent mutations that affect patient response to targeted therapies. We also highlight the importance of developing immunotherapies targeting novel and non-redundant epitopes or antigens in MM