Preclinical Development and Evaluation of Allogeneic CAR T Cells Targeting CD70 for the Treatment of Renal Cell Carcinoma

Panowski, Siler H.; Srinivasan, Surabhi; Tan, Nguyen Duy; Tacheva-Grigorova, Silvia K.; Smith, Bryan; Mak, Yvonne S.L.; Ning, Hongxiu; Villanueva, Jonathan; Wijewarnasuriya, Dinali; Lang, Shanshan; Melton, Zea; Ghosh, Adit; Dusséaux, Mathilde; Galetto, Román; Heyen, Jonathan R; Sai, Tao; Blarcom, Thomas Van; Chaparro‐Riggers, Javier; Sasu, Barbra J.

doi:10.1158/0008-5472.can-21-2931

Cited by 36 publications

(22 citation statements)

References 49 publications

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“…Previous reports of CD70KO CD70-specific CAR T cells did not show improved CAR T cell functionality 24 . We believe that the timing of the KO is crucial for the beneficial effect to occur.…”

Section: Discussionmentioning

confidence: 69%

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Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Munter

Buhl

Cock

et al. 2023

Preprint

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CD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CARs is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo by using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression by the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that endogenous CD70 interaction with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70KO CD70-specific nanoCAR T cells are protected from antigen induced exhaustion. Our data shows that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state which can be overcome by knocking out the specific target, in this case CD70.

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Section: Discussionmentioning

confidence: 69%

“…Two distinct classes of scFvs were defined based on their CD70-specific binding epitope. When used in CARs, these resulted in CAR T cells with different memory phenotypes, activation statuses and cytotoxic activity 24 .…”

Section: Introductionmentioning

confidence: 99%

Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Munter

Buhl

Cock

et al. 2023

Preprint

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“…Many patients with ccRCC showed abnormally high CD70 expression [ 135 ]. Therefore, targeting of CD70 function using CAR-T therapy thus far has only modest benefits, and positively evaluated [ 136 , 137 ].…”

Section: Cgas-sting and Baf Complexmentioning

confidence: 99%

Inflammatory Networks in Renal Cell Carcinoma

Kruk

Mamtimin

Braun

et al. 2023

Cancers

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Cancer-associated inflammation has been established as a hallmark feature of almost all solid cancers. Tumor-extrinsic and intrinsic signaling pathways regulate the process of cancer-associated inflammation. Tumor-extrinsic inflammation is triggered by many factors, including infection, obesity, autoimmune disorders, and exposure to toxic and radioactive substances. Intrinsic inflammation can be induced by genomic mutation, genome instability and epigenetic remodeling in cancer cells that promote immunosuppressive traits, inducing the recruitment and activation of inflammatory immune cells. In RCC, many cancer cell-intrinsic alterations are assembled, upregulating inflammatory pathways, which enhance chemokine release and neoantigen expression. Furthermore, immune cells activate the endothelium and induce metabolic shifts, thereby amplifying both the paracrine and autocrine inflammatory loops to promote RCC tumor growth and progression. Together with tumor-extrinsic inflammatory factors, tumor-intrinsic signaling pathways trigger a Janus-faced tumor microenvironment, thereby simultaneously promoting or inhibiting tumor growth. For therapeutic success, it is important to understand the pathomechanisms of cancer-associated inflammation, which promote cancer progression. In this review, we describe the molecular mechanisms of cancer-associated inflammation that influence cancer and immune cell functions, thereby increasing tumor malignancy and anti-cancer resistance. We also discuss the potential of anti-inflammatory treatments, which may provide clinical benefits in RCCs and possible avenues for therapy and future research.

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“…CD70 has also been found to be highly expressed in RCC and limited in normal tissue, making it an attractive target for CAR-T immunogenic solid tumors (44). Recently, Siler H Panowski et al (45) constructed CAR-T cells targeting CD70 single-chain antibodies. CD70-CAR-T cells showed strong antitumor activity against RCC cell lines and patient-derived xenograft mouse models.…”

Section: Renal Cell Carcinomamentioning

confidence: 99%

“…Recently, Siler H Panowski et al. ( 45 ) constructed CAR-T cells targeting CD70 single-chain antibodies. CD70-CAR- T cells showed strong antitumor activity against RCC cell lines and patient-derived xenograft mouse models.…”

Section: Car-t Cells For Urologic Neoplasmsmentioning

confidence: 99%

CAR-T Cells in the Treatment of Urologic Neoplasms: Present and Future

et al. 2022

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In recent years, with the breakthrough of CAR-T cells in the treatment of hematological tumors, they are increasingly being used to treat solid tumors, including urologic neoplasms. There are many relatively specific targets for urologic neoplasms, especially prostate cancer. Besides, urologic neoplasms tend to progress more slowly than tumors in other organs of the body, providing ample time for CAR-T cell application. Therefore, CAR-T cells technology has inherent advantages in urologic neoplasms. CAR-T cells in the treatment of urologic neoplasms have been extensively studied and preliminary achievements have been made. However, no breakthrough has been made due to the problems of targeting extra-tumor cytotoxicity and poor anti-tumor activity. we systematacially summarized the research actuality of CAR-T cells in urologic neoplasms, discussed the potential value and difficulties of the research. The application of CAR-T cells in the treatment of urologic neoplasms requires improvement of function through screening for better targets, modification of CAR structures, or in combination with other antitumor approaches.

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Preclinical Development and Evaluation of Allogeneic CAR T Cells Targeting CD70 for the Treatment of Renal Cell Carcinoma

Cited by 36 publications

References 49 publications

Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Inflammatory Networks in Renal Cell Carcinoma

CAR-T Cells in the Treatment of Urologic Neoplasms: Present and Future

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