Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma

Hegde, Meenakshi; Joseph, Sujith; Pashankar, Farzana; DeRenzo, Christopher; Sanber, Khaled; Navai, Shoba A.; Byrd, Tiara; Hicks, John; Xu, Mina L.; Gerken, Claudia; Kalra, Mamta; Robertson, Catherine; Zhang, Huimin; Shree, Ankita; Mehta, Birju; Dakhova, Olga; Salsman, Vita S.; Grilley, Bambi; Gee, Adrian P.; Dotti, Gianpietro; Heslop, Helen E.; Brenner, Malcolm K.; Wels, Winfried S.; Gottschalk, Stephen; Ahmed, Nabil

doi:10.1038/s41467-020-17175-8

Cited by 112 publications

(94 citation statements)

References 52 publications

(82 reference statements)

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“…In this singular case report, locally abundant rhabdomyosarcoma cells in the bone marrow supported CAR T expansion (following multiple CAR infusions) and 6 months of tumor control. Importantly, on-target/off-tumor toxicity was not reported [ 78 ]. This suggests that local accumulation of CAR T cells at the site of the tumor (here, in the bone marrow) improves the therapeutic index by limiting systemic exposure.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD19 CAR T cells potently redirected to kill solid tumor cells

Ambrose¹,

Su²,

Wu³

et al. 2021

PLoS ONE

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Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicity in vitro and in vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.

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Section: Discussionmentioning

confidence: 99%

Anti-CD19 CAR T cells potently redirected to kill solid tumor cells

Ambrose¹,

Su²,

Wu³

et al. 2021

PLoS ONE

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“…However, single case reports of patients with recurrent refractory solid tumors or brain tumors, who achieved CRs after CAR T cell therapy, have been reported (Table 1). 22,90 Clinical studies have also highlighted safety concerns. Two patients died of acute respiratory failure after having received lymphodepleting chemotherapy, a high dose (1 to 6 Â 10 10 ) of third-generation CAR T cells, and IL-2.…”

Section: Car T Cells For Solid Tumors and Brain Tumors-clinical Expermentioning

confidence: 99%

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

et al. 2020

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“…This study led to another phase I clinical trial (NCT00902044) testing anti-HER2 CAR T cells in combination with lymphodepleting chemotherapy in refractory/metastatic HER2-positive sarcoma patients. In an update of the trial, it was reported that one patient with metastatic rhabdomyosarcoma showed complete response, while stable disease was recorded in 2 of 6 patients and 3 of 6 had progressive disease [ 80 , 81 ]. This warrants further studies in a larger cohort of patients.…”

Section: Adoptive Transfer Of Genetically Modified T Cellsmentioning

confidence: 99%

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

Chew

Chan

Simpson

et al. 2020

Cancers

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Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors hampering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.

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Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma

Cited by 112 publications

References 52 publications

Anti-CD19 CAR T cells potently redirected to kill solid tumor cells

Anti-CD19 CAR T cells potently redirected to kill solid tumor cells

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

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