Evidence map›Paper›PMID 38007238›Full record

ArticleJournal for immunotherapy of cancer2023

Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies.

William C Temple, Matthew A Nix, Akul Naik, Adila Izgutdina, Benjamin J Huang, Gianina Wicaksono, Paul Phojanakong, Juan Antonio Camara Serrano, Elizabeth P Young, Emilio Ramos and 7 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal for immunotherapy of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
4.8field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 21 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 2 institutions in 1 country.

William C TempleDepartment of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA.ORCID 0000-0003-3375-2703
Matthew A NixDepartment of Laboratory Medicine, University of California, San Francisco, California, USA.
Akul NaikDepartment of Laboratory Medicine, University of California, San Francisco, California, USA.
Adila IzgutdinaDepartment of Laboratory Medicine, University of California, San Francisco, California, USA.
Benjamin J HuangDepartment of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA.
Gianina WicaksonoDepartment of Laboratory Medicine, University of California, San Francisco, California, USA.
Paul PhojanakongHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
Juan Antonio Camara SerranoHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
Elizabeth P YoungDepartment of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA.
Emilio RamosDepartment of Laboratory Medicine, University of California, San Francisco, California, USA.
Fernando SalangsangHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
Veronica SteriHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
Simayijiang XirenayiDepartment of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA.
Michelle HermistonDepartment of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA.
Aaron C LoganDepartment of Medicine, Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, California, USA.
Elliot StieglitzDepartment of Pediatrics, Division of Hematology/Oncology, University of California, UCSF Benioff Children's Hospital, San Francisco, California, USA.
Arun P WiitaDepartment of Laboratory Medicine, University of California, San Francisco, California, USA arun.wiita@ucsf.edu.
University of California, San Francisco · USUCSF Benioff Children's Hospital · US

Funding

Translational InformaticsP30CA082103 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Kate Taylor Shumate · 1999 to 2026
$209.7M
Research Training in Childhood CancerT32CA128583 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Eric Alejandro Sweet-Cordero · 2007 to 2026
$6.0M
Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML.K08CA256489 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HUANG, BENJAMIN · 2021 to 2025
$1.2M
NCI NIH HHS K08 CA256489NCI NIH HHS P30 CA082103NCI NIH HHS T32 CA128583
6 · The paper itself

Abstract

backgroundApproximately 50% of patients who receive anti-CD19 CAR-T cells relapse, and new immunotherapeutic targets are urgently needed. We recently described CD72 as a promising target in B-cell malignancies and developed nanobody-based CAR-T cells (nanoCARs) against it. This cellular therapy design is understudied compared with scFv-based CAR-T cells, but has recently become of significant interest given the first regulatory approval of a nanoCAR in multiple myeloma.

methodsWe humanized our previous nanobody framework regions, derived from llama, to generate a series of humanized anti-CD72 nanobodies. These nanobody binders were inserted into second-generation CD72 CAR-T cells and were evaluated against preclinical models of B cell acute lymphoblastic leukemia and B cell non-Hodgkin's lymphoma in vitro and in vivo. Humanized CD72 nanoCARs were compared with parental ("NbD4") CD72 nanoCARs and the clinically approved CD19-directed CAR-T construct tisangenlecleucel. RNA-sequencing, flow cytometry, and cytokine secretion profiling were used to determine differences between the different CAR constructs. We then used affinity maturation on the parental NbD4 construct to generate high affinity binders against CD72 to test if higher affinity to CD72 improved antitumor potency.

resultsToward 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, including patient-derived samples after CD19 CAR-T relapse. Potentially underpinning improved potency, H24 has moderately higher binding affinity to CD72 compared with a fully llama framework. However, further affinity maturation (K

conclusionThis work supports translation of H24 CD72 nanoCARs for refractory B-cell malignancies, reveals potential mechanisms of resistance, and unexpectedly demonstrates that nanoCAR potency can be improved by framework alterations alone. These findings may have implications for future engineering of nanobody-based cellular therapies.

Indexed as

Burkitt LymphomaCamelids, New WorldReceptors, Chimeric AntigenAnimalsAntigens, CDAntigens, Differentiation, B-LymphocyteHumansImmunotherapy, AdoptiveRecurrenceT-LymphocytesAntigens, CDAntigens, Differentiation, B-LymphocyteCD72 protein, humanReceptors, Chimeric AntigenCell EngineeringHematologic NeoplasmsImmunotherapyReceptors, Chimeric AntigenTranslational Medical Research

Identifiers

PMID38007238
PMCPMC10680002
OpenAlexW4389001206

What OpenQuestion holds

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LicenceCC BY-NC
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.