Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis

Vitanza, Nicholas A.; Johnson, Adam; Wilson, Ashley; Brown, Christopher; Yokoyama, Jason K.; Künkele, Annette; Chang, Cindy A.; Rawlings‐Rhea, Stephanie D.; Huang, Wenjun; Seidel, Kristy; Albert, Catherine M.; Pinto, Navin; Gust, Juliane; Finn, Laura S.; Ojemann, Jeffrey G.; Wright, Jason N.; Orentas, Rimas J.; Baldwin, Michael; Gardner, Rebecca; Jensen, Michael C.; Park, Julie R.

doi:10.1038/s41591-021-01404-8

Cited by 159 publications

(146 citation statements)

References 50 publications

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“…The CAR-T anti-tumor activity and “on-target, off-tumor toxicity” are dependent on the target antigen density. Locoregional HER2-specific CAR-T injection through intra-CNS delivery was well tolerated and showed no evidence of “on-target, off-tumor toxicity” ( 22 ). Another study also showed that side effects could be avoided by optimizing CAR design, decreasing the dose of CAR-T cells, and improving the treatment plan (such as omitting post-infusion IL-2 and lymphodepleting chemotherapy) ( 23 ).…”

Section: Resultsmentioning

confidence: 99%

“…"SCTransform" and "RunHarmony" functions were used to remove the batch effect as mentioned above. Clusters were calculated using the FindClusters function with a resolution of 0.5, and the B lineagerelated subpopulations were extracted by "subset(object, idents = c (0, 1,3,4,5,8,10,11,12,13,14,15,17,18,19,20,21,22))". Finally, the expression level was compared using the "Dotplot" function with "group.by = "orig.ident".…”

Section: Comparison Of Gene Expression Profiles Of Lymphomas With Rlnmentioning

confidence: 99%

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Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Zhang

Cao

et al. 2021

Front. Immunol.

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Cellular immunotherapy represented by CD19-directed chimeric antigen receptor T (CAR-T) cells has achieved great success in recent years. An increasing number of CAR-T therapies are being developed for cancer treatment, but the frequent and varied adverse events, such as “on-target, off-tumor toxicity”, limit CAR-T application. Here, we identify the target antigen expression patterns of CAR therapies in 18 tissues and organs (peripheral blood mononuclear cells, bone marrow, lymph nodes, spleen, heart, ascending aortic tissue, trachea, lung, skin, kidney, bladder, esophagus, stomach, small intestine, rectum, liver, common bile duct, and pancreas) from healthy human samples. The atlas determines target antigens expressed on some normal cell types, which facilitates elucidating the cause of “on-target, off-tumor toxicity” in special tissues and organs by targeting some antigens, but not others. Moreover, we describe the target antigen expression patterns of B-lineage-derived malignant cells, acute myeloid leukemia (AML), and solid tumors. Overall, the present study indicates the pathogenesis of “on-target, off-tumor toxicity” during CAR therapies and provides guidance on taking preventive measures during CAR treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Comparison Of Gene Expression Profiles Of Lymphomas With Rlnmentioning

confidence: 99%

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Zhang

Cao

et al. 2021

Front. Immunol.

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“…However, the HER2-VST CARs did not expand in the peripheral blood and clinical efficacy was limited with a median OS of 11.1 months. An interim analysis of a phase 1 clinical trial using locoregional delivery of HER2-specific CAR T cells recently reported no dose-limiting toxicity of multiple CAR T cell infusions and demonstrated highly elevated interferon-induced C-X-C motif chemokine ligand 10 (CXCL10) and CC-chemokine ligand 2 (CCL2) levels in the cerebrospinal fluid (CSF) after CAR T cell infusion [ 43 ]. Magnetic resonance (MR) imaging showed vasogenic edema and local intensified contrast enhancement, indicating an inflammatory response called pseudoprogression.…”

Section: Glioma Antigens For Car-engineered T Cell Therapymentioning

confidence: 99%

Genetically Modified Cellular Therapies for Malignant Gliomas

Kilian

Bunse

Wick

et al. 2021

IJMS

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Despite extensive preclinical research on immunotherapeutic approaches, malignant glioma remains a devastating disease of the central nervous system for which standard of care treatment is still confined to resection and radiochemotherapy. For peripheral solid tumors, immune checkpoint inhibition has shown substantial clinical benefit, while promising preclinical results have yet failed to translate into clinical efficacy for brain tumor patients. With the advent of high-throughput sequencing technologies, tumor antigens and corresponding T cell receptors (TCR) and antibodies have been identified, leading to the development of chimeric antigen receptors (CAR), which are comprised of an extracellular antibody part and an intracellular T cell receptor signaling part, to genetically engineer T cells for antigen recognition. Due to efficacy in other tumor entities, a plethora of CARs has been designed and tested for glioma, with promising signs of biological activity. In this review, we describe glioma antigens that have been targeted using CAR T cells preclinically and clinically, review their drawbacks and benefits, and illustrate how the emerging field of transgenic TCR therapy can be used as a potent alternative for cell therapy of glioma overcoming antigenic limitations.

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“…CAR T cell administration can be made hematogenously, or via the cerebral spinal fluid, or locally in the tumor cavity. Brain tumors are currently one of the most common solid tumor types undergoing clinical trial testing for CAR T cell efficacy and have shown early promise in treating “glioblastomas” ( 178 , 179 ). Multiple clinical trials are evaluating the efficacy of CAR T cell therapy in solid tumors.…”

Section: Treatmentmentioning

confidence: 99%

Advanced Magnetic Resonance Imaging in Pediatric Glioblastomas

2021

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The shortly upcoming 5th edition of the World Health Organization Classification of Tumors of the Central Nervous System is bringing extensive changes in the terminology of diffuse high-grade gliomas (DHGGs). Previously “glioblastoma,” as a descriptive entity, could have been applied to classify some tumors from the family of pediatric or adult DHGGs. However, now the term “glioblastoma” has been divested and is no longer applied to tumors in the family of pediatric types of DHGGs. As an entity, glioblastoma remains, however, in the family of adult types of diffuse gliomas under the insignia of “glioblastoma, IDH-wildtype.” Of note, glioblastomas still can be detected in children when glioblastoma, IDH-wildtype is found in this population, despite being much more common in adults. Despite the separation from the family of pediatric types of DHGGs, what was previously labeled as “pediatric glioblastomas” still remains with novel labels and as new entities. As a result of advances in molecular biology, most of the previously called “pediatric glioblastomas” are now classified in one of the four family members of pediatric types of DHGGs. In this review, the term glioblastoma is still apocryphally employed mainly due to its historical relevance and the paucity of recent literature dealing with the recently described new entities. Therefore, “glioblastoma” is used here as an umbrella term in the attempt to encompass multiple entities such as astrocytoma, IDH-mutant (grade 4); glioblastoma, IDH-wildtype; diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; and high grade infant-type hemispheric glioma. Glioblastomas are highly aggressive neoplasms. They may arise anywhere in the developing central nervous system, including the spinal cord. Signs and symptoms are non-specific, typically of short duration, and usually derived from increased intracranial pressure or seizure. Localized symptoms may also occur. The standard of care of “pediatric glioblastomas” is not well-established, typically composed of surgery with maximal safe tumor resection. Subsequent chemoradiation is recommended if the patient is older than 3 years. If younger than 3 years, surgery is followed by chemotherapy. In general, “pediatric glioblastomas” also have a poor prognosis despite surgery and adjuvant therapy. Magnetic resonance imaging (MRI) is the imaging modality of choice for the evaluation of glioblastomas. In addition to the typical conventional MRI features, i.e., highly heterogeneous invasive masses with indistinct borders, mass effect on surrounding structures, and a variable degree of enhancement, the lesions may show restricted diffusion in the solid components, hemorrhage, and increased perfusion, reflecting increased vascularity and angiogenesis. In addition, magnetic resonance spectroscopy has proven helpful in pre- and postsurgical evaluation. Lastly, we will refer to new MRI techniques, which have already been applied in evaluating adult glioblastomas, with promising results, yet not widely utilized in children.

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Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis

Cited by 159 publications

References 50 publications

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Genetically Modified Cellular Therapies for Malignant Gliomas

Advanced Magnetic Resonance Imaging in Pediatric Glioblastomas

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