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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143181 | GEO | 2021/12/17

REPOSITORIES: GEO

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Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies II

Project description:Alternate strategies are needed for B-cell malignancy patients relapsing after CD19-targeted immunotherapy. Here, integrated cell surface proteomics and epigenetic analysis initially revealed CD72 as an optimal target for poor-prognosis MLL-rearranged B-ALL, which we further found to be expressed widely across B-cell malignancies. Using a recently-described, fully-in vitro system we selected CD72-specific nanobodies, incorporated them into CARs, and demonstrated robust activity against B-cell malignancy models, including CD19 loss. “Antigen escape profiling” modeled membrane proteome changes in the context of CD72 loss while pharmacologic SHIP1 inhibition increased CD72 surface density. We establish CD72-nanobody CAR T’s as a promising therapy for refractory B-cell malignancies.

2021-12-17 | GSE143179 | GEO

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies I

2021-12-17 | GSE142447 | GEO

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

2022-02-15 | PXD016800 | Pride

Surface Proteomics Reveals CD72 as a Target for <i>In Vitro</i>-Evolved Nanobody-Based CAR-T Cells in <i>KMT2A/MLL1</i>-Rearranged B-ALL.

Project description:Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully in vitro system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL. SIGNIFICANCE: Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully in vitro nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development.This article is highlighted in the In This Issue feature, p. 1861.

| S-EPMC8338785 | biostudies-literature

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

Project description:Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies

| PRJNA599148 | ENA

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies I

Project description:Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies I

| PRJNA597032 | ENA

Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies II

Project description:Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in refractory B-cell malignancies II

| PRJNA599156 | ENA

Framework humanization increases the affinity and potency of anti-CD72 nanobody-based CAR-T cells for B-cell malignancies

Project description:Anti-CD19 CAR T cells can induce remissions in some patients with B-cell malignancies. However, new immunotherapeutic targets are urgently needed for the many who relapse. We recently described CD72 as a promising target in B-cell leukemia and lymphoma, developing fully synthetic nanobody-based CAR-T cells (nanoCARs) against this antigen. Toward clinical translation, here we humanize our previous nanobody framework regions, derived from llama, and surprisingly discover a clone ("H24") with enhanced potency against B-cell tumors both in vitro and in vivo. In vitro, H24 nanoCARs showed improved cytokine secretion and favorable immunophenotypic properties. RNA sequencing before and after tumor exposure reveals humanized H24 CD72 nanoCARs have unique transcriptional programs compared to CD19 CAR T cells. We further find that H24 nanoCARs lead to sustained CD72 downregulation on tumors treated in vivo. Underpinning this improved potency, H24 had higher binding affinity to CD72 compared to a fully llama framework. Further affinity maturation moderately increased cytotoxicity versus antigen-low tumors. This work supports clinical translation of H24 CD72 nanoCARs, reveals potential mechanisms of resistance to this cellular therapy, and unexpectedly demonstrates that nanoCAR potency can be improved by framework alterations alone, without any change to the complementarity determining regions (CDRs) of the nanobody sequence.

2022-12-29 | GSE218791 | GEO

Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice.

Project description:Chimeric antigen receptor (CAR) T cell therapy has been successful in clinical trials against hematological cancers, but has experienced challenges in the treatment of solid tumors. One of the main difficulties lies in a paucity of tumor-specific targets that can serve as CAR recognition domains. We therefore focused on developing VHH-based, single-domain antibody (nanobody) CAR T cells that target aspects of the tumor microenvironment conserved across multiple cancer types. Many solid tumors evade immune recognition through expression of checkpoint molecules, such as PD-L1, that down-regulate the immune response. We therefore targeted CAR T cells to the tumor microenvironment via the checkpoint inhibitor PD-L1 and observed a reduction in tumor growth, resulting in improved survival. CAR T cells that target the tumor stroma and vasculature through the EIIIB+ fibronectin splice variant, which is expressed by multiple tumor types and on neovasculature, are likewise effective in delaying tumor growth. VHH-based CAR T cells can thus function as antitumor agents for multiple targets in syngeneic, immunocompetent animal models. Our results demonstrate the flexibility of VHH-based CAR T cells and the potential of CAR T cells to target the tumor microenvironment and treat solid tumors.

| S-EPMC6475367 | biostudies-literature

Allogenic and Autologous anti-CD7 CAR-T cell Therapies in Relapsed or Refractory T-Cell Malignancies

Project description:Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7- 14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.

2023-03-25 | GSE227828 | GEO

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