DCLK1 Monoclonal Antibody-Based CAR-T Cells as a Novel Treatment Strategy against Human Colorectal Cancers

Sureban, Sripathi M.; Berahovich, Robert; Zhou, Hua; Xu, Shuning; Wu, Lijun; Ding, Kai; May, Randal; Qu, Dongfeng; Bannerman-Menson, Edwin; Golubovskaya, Vita M.; Houchen, Courtney W.

doi:10.3390/cancers12010054

Cited by 43 publications

(43 citation statements)

References 56 publications

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“…According to previous evidence, raised levels of Doublecortin-like kinase 1 (DCLK1) expression in human colorectal tumors are associated with higher mortality rates. A recent report revealed that DCLK1’s targeted CAR-T therapy effectively eradicates primary and metastatic colon cancer cells [ 105 ].…”

Section: Car T Cell Therapy In Solid Tumors: Recent Advancesmentioning

confidence: 99%

CAR T cells in solid tumors: challenges and opportunities

et al. 2021

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Background CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

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Section: Car T Cell Therapy In Solid Tumors: Recent Advancesmentioning

confidence: 99%

CAR T cells in solid tumors: challenges and opportunities

et al. 2021

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“…A further study using anti-EpCAM CAR T cells for local treatment of peritoneal carcinomatosis in xenograft mice demonstrated the efficacy of this approach for the treatment of gastrointestinal and gynecologic malignancies [ 105 ]. Numerous preclinical studies have indicated other surface markers potentially useful to identify or target CSCs: CD90, ALDH, CD47, CD44, CD24, microtubule-associated doublecortin-like kinase 1 (DCLK1) that are expressed in multiple cancer types with a higher expression in CSCs compared to other bulk tumor cells [ 82 , 97 , 106 , 107 ]. DCLK1 has been described as a CSC associated antigen in colon, pancreatic [ 108 , 109 , 110 ] and even in Cholangiocarcinoma (CCA) tumors [ 111 ].…”

Section: Cellular Immunotherapy Targeting Cscsmentioning

confidence: 99%

Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective

Donini

Rotolo

Proment

et al. 2021

Cells

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The term “cancer stem cells” (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to recognition and targeting by the immune system is a relevant issue and matter of investigation, especially considering the multiple emerging immunotherapy strategies. Adoptive cellular immunotherapies, especially those strategies encompassing the genetic redirection with chimeric antigen receptors (CAR), hold relevant promise in several tumor settings and might in theory provide opportunities for selective elimination of CSC subsets. Initial dedicated preclinical studies are supporting the potential targeting of CSCs by cellular immunotherapies, indirect evidence from clinical studies may be derived and new studies are ongoing. Here we review the main issues related to the putative immunogenicity of CSCs, focusing on and highlighting the existing evidence and opportunities for cellular immunotherapy approaches with T and non-T antitumor lymphocytes.

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“…Utilizing well-characterized CSC markers makes it possible to develop CAR-T cells with the potential to eliminate CSCs. As a CAR-T target, DCLK1 single-chain antibody variable fragment (CBT-511), showed a prominent cytotoxic effect against tumor cells and reduced tumor growth in CRC [ 27 ]. CBT-511 also increased IFN-γ release in CRC cells (2D and 3D).…”

Section: Development Of Dclk1-targeted Therapeutic Agents and Biolmentioning

confidence: 99%

“…Furthermore, several recent studies show that DCLK1 affects tumor growth and metastasis via regulating TAM and immune checkpoint. Finally, monoclonal antibodies and chimeric antigen receptor T-Cells (CAR-T) based on DCLK1 have demonstrated potential as novel cancer immunotherapies [ 26 , 27 , 28 ]. Herein we review key advances in the understanding of DCLK1 and DCLK1+ TCs function in the context of the tumor and immune microenvironment and discuss future directions for DCLK1-based research and development.…”

Section: Introductionmentioning

confidence: 99%

Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment

Cao

Weygant

Chandrakesan

et al. 2020

Cancers

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Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.

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DCLK1 Monoclonal Antibody-Based CAR-T Cells as a Novel Treatment Strategy against Human Colorectal Cancers

Cited by 43 publications

References 56 publications

CAR T cells in solid tumors: challenges and opportunities

CAR T cells in solid tumors: challenges and opportunities

Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective

Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment

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