Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

Smith, Jenessa B.; Lanitis, Evripidis; Dangaj, Denarda; Buza, Elizabeth L.; Poussin, Mathilde; Stashwick, Caitlin; Scholler, Nathalie; Powell, Daniel J.

doi:10.1038/mt.2016.149

Cited by 47 publications

(35 citation statements)

References 54 publications

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“…A recent study by Smith and colleagues found that while T cells expressing a CAR specific for B7-H4 exhibit antitumor activity in a mouse xenograft transplant model, mice reproducibly developed delayed, lethal toxicity 6 to 8 weeks after treatment. Postmortem analysis of mice showed B7-H4 expression by normal ductal and mucosal epithelial tissue coincided with severe histologic damage, demonstrating that B7-H4 expression by normal tissues was not low enough to avoid off-tumor effects (60). Although Leong and colleagues did not observe off-target activity after administration of anti-B7-H4 antibody-drug conjugate, they did not confirm recognition of mouse B7-H4 by the human antibody used in the drug conjugate.…”

Section: B7-h4-a Novel Target For Therapy?mentioning

confidence: 98%

Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target

MacGregor

Ohashi

2017

Clinical Cancer Research

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With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment antitumor responses by targeting other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies. This high expression by tumors in combination with its low or absent protein expression in normal tissues makes B7-H4 an attractive immunotherapeutic target. Preclinical investigation into B7-H4-specific chimeric antigen receptor (CAR) T cells, antibody-mediated blockade of B7-H4, and anti-B7-H4 drug conjugates has shown antitumor efficacy in mouse models. The first clinical trials have been completed to assess the safety and efficacy of a B7-H4 fusion protein in ameliorating rheumatoid arthritis. .

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Section: B7-h4-a Novel Target For Therapy?mentioning

confidence: 98%

Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target

MacGregor

Ohashi

2017

Clinical Cancer Research

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“…A CAR T cell‐B7x therapy was tested in a murine ovarian cancer model. It was not only very effective against human ovarian tumor xenografts but also had delayed lethal toxicity . Post mortem analysis showed that the normal tissues showed increased expression of B7x protein.…”

Section: B7xmentioning

confidence: 99%

“…It was not only very effective against human ovarian tumor xenografts but also had delayed lethal toxicity. 96 Post mortem analysis showed that the normal tissues showed increased expression of B7x protein. This late toxicity may be overcome by means of a switch receptor/chimera or by using suicidal gene therapy before the delayed onset of normal organ toxicity which is distinct from the anti-tumor effects.…”

Section: Cancermentioning

confidence: 99%

The third group of the B7‐CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7‐H3

Janakiram

Shah

Liu

et al. 2017

Immunological Reviews

195

115

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Summary The B7-CD28 family of ligands and receptors play important roles in T cell costimulation and coinhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules [B7-H3 (CD276), B7x (B7-H4/B7S1) and HHLA2 (B7H7/B7-H5)/TMIGD2 (IGPR-1/CD28H)] of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure and function of B7-H3, B7x, HHLA2 and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.

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“…Therefore, the therapeutic approaches targeting these antigens require antibody dose control for harnessing cytotoxic effector cells. B7-H4-targeted CAR-T-cell treatment showed lethal toxicity including a delayed GVHD in a mouse model (37), and a clinical trial using trastuzumabbased CAR-T cells resulted in patient death and was aborted (38). These reported adverse events suggest that the strict regulation of effector function is important for clinical use.…”

Section: Discussionmentioning

confidence: 99%

A T-cell–engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer

Iizuka

Nonomura

Ashizawa

et al. 2019

Clinical Cancer Research

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Purpose: The B7 homolog 4 (B7-H4, VTCN1) is an immune checkpoint molecule that negatively regulates immune responses and is known to be overexpressed in many human cancers. Previously, we generated a mouse anti-human B7-H4 mAb that did not have a significant antitumor effect in vivo probably because of molecule instability. In this study, we designed a B7-H4/CD3-bispecific antibody (BsAb) and investigated its antitumor activity in vitro and in vivo using a humanized mouse model. Experimental Design: cDNAs of the antibody-binding fragment (Fab)-single-chain variable fragment (scFv) and scFv-scFv of the anti-B7-H4/CD3 BsAb were synthesized, and the BsAb antibodies were produced in HEK293 cells. The antitumor activity against human breast cancer cells by human peripheral blood mononuclear cells (hPBMC) with BsAb was measured by lactate dehydrogenase release in vitro, and in vivo using hPBMC-transplanted MHC class I-and class II-deficient NOG mice. Results: hPBMCs with anti-B7-H4/CD3 BsAbs successfully lysed the human breast cancer cell line MDA-MB-468 (EC 50 : 0.2 ng/mL) and other B7-H4 þ cell lines in vitro. When BsAb was injected in a humanized mouse model, there was an immediate and strong antitumor activity against MDA-MB-468, HCC-1954, and HCC-1569 tumors and CD8 þ and granzyme B þ CTL infiltration into the tumor, and there were no adverse effects after long-term observation. CD8 þ T-cell depletion by an anti-CD8 antibody mostly reduced the antitumor effect of BsAb in vivo. Conclusions: An anti-B7-H4/CD3 BsAb may be a good therapeutic tool for patients with B7-H4 þ breast cancers.

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Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

Cited by 47 publications

References 54 publications

Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target

Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target

The third group of the B7‐CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7‐H3

A T-cell–engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer

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