bims-limsir 2022-10-30 papers

Biomedicines. 2022 Sep 30. pii: 2441. [Epub ahead of print]10(10):

Recent Advances in the Development of Anti-FLT3 CAR T-Cell Therapies for Treatment of AML.

Maya Graham Pedersen, Bjarne Kuno Møller, Rasmus O Bak.

Following the success of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapies against B-cell malignancies, the CAR T-cell approach is being developed towards other malignancies like acute myeloid leukemia (AML). Treatment options for relapsed AML patients are limited, and the upregulation of the FMS-like tyrosine kinase 3 (FLT3) in malignant T-cells is currently not only being investigated as a prognostic factor, but also as a target for new treatment options. In this review, we provide an overview and discuss different approaches of current anti-FLT3 CAR T-cells under development. In general, these therapies are effective both in vitro and in vivo, however the safety profile still needs to be further investigated. The first clinical trials have been initiated, and the community now awaits clinical evaluation of the approach of targeting FLT3 with CAR T-cells.

Keywords: AML; CAR; CAR T; FLT3; FLT3L; FMS-like tyrosine kinase-3; chimeric antigen receptor; leukemia

DOI: https://doi.org/10.3390/biomedicines10102441

Cancers (Basel). 2022 Oct 18. pii: 5108. [Epub ahead of print]14(20):

Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors.

Francesco Boccalatte, Roberto Mina, Andrea Aroldi, Sarah Leone, Carter M Suryadevara, Dimitris G Placantonakis, Benedetto Bruno.

Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of specific target antigens and severe, potentially fatal, toxicities caused by on-target off-tumor toxicities constitute major hurdles. Furthermore, the tumor microenvironment is usually characterized by chronic inflammation, the presence of immunosuppressive molecules, and immune cells that can reduce CAR T cell efficacy and facilitate antigen escape. Nonetheless, solid tumors are under investigation as possible targets despite their complexity, which represents a significant challenge. In preclinical mouse models, CAR T cells are able to efficiently recognize and kill several tumor xenografts. Overall, in the next few years, there will be intensive research into optimizing novel cell therapies to improve their effector functions and keep untoward effects in check. In this review, we provide an update on the state-of-the-art CAR T cell therapies in solid tumors, focusing on the preclinical studies and preliminary clinical findings aimed at developing optimal strategies to reduce toxicity and improve efficacy.

Keywords: adoptive immunotherapy; chimeric antigen; chimeric antigen receptor (CAR) T cell; receptors; solid tumors; tumor microenvironment; xenograft models

DOI: https://doi.org/10.3390/cancers14205108

Front Immunol. 2022 ;13 983934

Case report: CD19-directed CAR-T cell therapy combined with BTK inhibitor and PD-1 antibody against secondary central nervous system lymphoma.

Wenqi Zhang, Chen Huang, Ruixia Liu, Huichao Zhang, Weijing Li, Shaoning Yin, Lianjing Wang, Wei Liu, Lihong Liu.

Current therapeutic strategies for central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) are extremely limited. Secondary central nervous system lymphoma (SCNSL) also shows a grave prognosis and high mortality. This report describes a young female patient with DLBCL and CNS relapse who received low-dose CD19-directed chimeric antigen receptor T (CAR-T) cell therapy followed with Bruton's tyrosine kinase inhibitor and programmed cell death protein 1 antibody after several lines of chemotherapy. However, limited reports on CAR-T cell therapy are applied for SCNSL, particularly those in combination with targeted agents. The current treatment combination for this case provides a new regimen for CNS relapse from DLBCL.
Clinical Trial Registration: ClinicalTrials.gov number, NCT04666168.

Keywords: BTK inhibitor; CD19 CAR-T cell therapy; PD-1 antibody; scnsl; tislelizumab; zanubrutinib

DOI: https://doi.org/10.3389/fimmu.2022.983934

Sci Transl Med. 2022 Oct 26. 14(668): eabq3010

Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia.

TT52 CRISPR-CAR group

Genome editing of allogeneic T cells can provide "off-the-shelf" alternatives to autologous chimeric antigen receptor (CAR) T cell therapies. Disruption of T cell receptor α chain (TRAC) to prevent graft-versus-host disease (GVHD) and removal of CD52 (cluster of differentiation 52) for a survival advantage in the presence of alemtuzumab have previously been investigated using transcription activator-like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 editing and linked CAR expression to multiplexed DNA editing of TRAC and CD52 through incorporation of self-duplicating CRISPR guide RNA expression cassettes within the 3' long terminal repeat of a CAR19 lentiviral vector. Three cell banks of TT52CAR19 T cells were generated and cryopreserved. A phase 1, open-label, non-randomized clinical trial was conducted and treated six children with relapsed/refractory CD19-positive B cell acute lymphoblastic leukemia (B-ALL) (NCT04557436). Lymphodepletion included fludarabine, cyclophosphamide, and alemtuzumab and was followed by a single infusion of 0.8 × 106 to 2.0 × 106 CAR19 T cells per kilogram with no immediate toxicities. Four of six patients infused with TT52CAR19 T cells exhibited cell expansion, achieved flow cytometric remission, and then proceeded to receive allogeneic stem cell transplantation. Two patients required biological intervention for grade II cytokine release syndrome, one patient developed transient grade IV neurotoxicity, and one patient developed skin GVHD, which resolved after transplant conditioning. Other complications were within expectations, and primary safety objectives were met. This study provides a demonstration of the feasibility, safety, and therapeutic potential of CRISPR-engineered immunotherapy.

DOI: https://doi.org/10.1126/scitranslmed.abq3010

Immunother Adv. 2022 ;2(1): ltac014

Current and future perspectives of chimeric antigen receptors against glioblastoma.

Josephine Zhang, Jesús A Siller-Farfán.

Glioblastoma multiforme (GBM) is the most malignant form of cancer in the central nervous system; even with treatment, it has a 5-year survival rate of 7.2%. The adoptive cell transfer (ACT) of T cells expressing chimeric antigen receptors (CARs) has shown a remarkable success against hematological malignancies, namely leukemia and multiple myeloma. However, CAR T cell therapy against solid tumors, and more specifically GBM, is still riddled with challenges preventing its widespread adoption. Here, we first establish the obstacles in ACT against GBM, including on-target/off-tumor toxicity, antigen modulation, tumor heterogeneity, and the immunosuppressive tumor microenvironment. We then present recent preclinical and clinical studies targeting well-characterized GBM antigens, which include the interleukin-13 receptor α2 and the epidermal growth factor receptor. Afterward, we turn our attention to alternative targets in GBM, including less-explored antigens such as B7-H3 (CD276), carbonic anhydrase IX, and the GD2 ganglioside. We also discuss additional target ligands, namely CD70, and natural killer group 2 member D ligands. Finally, we present the possibilities afforded by novel CAR architectures. In particular, we examine the use of armored CARs to improve the survival and proliferation of CAR T cells. We conclude by discussing the advantages of tandem and synNotch CARs when targeting multiple GBM antigens.

Keywords: adoptive cell therapy; adoptive cell transfer; cancer immunotherapy; chimeric antigen receptors; glioblastoma; solid tumors

DOI: https://doi.org/10.1093/immadv/ltac014