Clinical Evaluation of ErbB-Targeted CAR T-Cells, Following Intracavity Delivery in Patients with ErbB-Expressing Solid Tumors

Our plain-English summary of Clinical Evaluation of ErbB-Targeted CAR T-Cells, Following Intracavity Delivery in Patients with ErbB-Expressing Solid Tumors, by S. Papa, M. van Schalkwyk, J. Maher (Methods in Molecular Biology, 2015).

The study

• Authors: S. Papa, M. van Schalkwyk, J. Maher
• Journal: Methods in Molecular Biology
• Published: 2015;1317:365-82
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Adoptive cell therapy using gene-modified T-cells has achieved impressive results in the treatment of B-cell malignancies. However, the development of similar strategies to treat solid tumors raises challenges with respect to tumor antigen selection and the achievement of efficient T-cell homing, survival and sustained effector function within the tumor microenvironment. To address these challenges, we have developed a gene-modified cellular therapy called T4 immunotherapy. To generate T4 immunotherapy, autologous T-cells are engineered by retroviral transduction to co-express two transgenes: (1) a chimeric antigen receptor (CAR), T1E28z, targeted against a range of ErbB homodimers and heterodimers and (2) a chimeric cytokine receptor, 4αβ, that allows the selective ex vivo expansion of engineered cells using interleukin-4. Targeting of the extended ErbB network using CAR T-cells is supported by prevalence of ErbB dysregulation in diverse solid tumors and the clinical impact of monoclonal antibody therapy directed against members of this family. However, the key obstacle to effective clinical translation is risk of on-target toxicity owing to the lower level expression of ErbB family members in many healthy tissues. To de-risk T4 immunotherapy in man, we are undertaking a trial in patients with locally advanced or recurrent head and neck squamous cell carcinoma. In that setting, engineered T-cells are injected directly into the tumor without prior lymphodepletion, an approach that we believe will minimize risk of toxicity. This chapter outlines how we plan to advance the development of T4 immunotherapy thereafter in Phase II clinical testing. In that setting, regional (intracavitary) approaches will be used to administer this therapy to patients with epithelial ovarian cancer and malignant pleural mesothelioma.

In plain English

This book chapter reported no new results; the trials it described had not yet taken place. It set out the authors' plans for testing an experimental treatment, T4 immunotherapy, after a first trial in head and neck cancer. The treatment uses a patient's own T-cells (white blood cells), genetically changed to target ErbB proteins found on many cancers. Depending on that first trial, a small safety study would begin with three patients with malignant pleural mesothelioma and three with high-grade serous ovarian cancer, given the cells by catheter into the chest or abdominal cavity. Three more per disease would follow, after cyclophosphamide, if no serious adverse events occurred. Randomized Phase II trials were planned later. The chapter did not study asbestos exposure. The authors named as the greatest challenge the risk that the cells would attack ErbB proteins in healthy tissues. They also named the tumors' immune-suppressing environment, and the closing of the pleural space by usual mesothelioma care. The authors concluded that these planned studies offered a pragmatic vision for developing such a therapy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Methods chapter describing planned clinical trials that had not yet been carried out: a small Phase IB safety study and open-label randomized Phase II trials. It reports no new study results. Earlier work, including mouse experiments, is cited from previously published studies.
• Who was studied: Planned, not yet enrolled. The Phase IB study depends on the outcome of the preceding head and neck cancer trial. It would start with three patients with malignant pleural mesothelioma (MPM) and three with high-grade serous ovarian cancer (HG-SOC). A further three per disease would be treated after cyclophosphamide if no serious adverse events occurred. A single serious adverse event would expand a group to a maximum of six patients. The authors are at King's College London and Guy's and St Thomas' (UK).
• Exposure: Not asbestos. The intervention is T4 immunotherapy: the patient's own T-cells, engineered to carry an ErbB-targeted chimeric antigen receptor (T1E28z) and an IL-4-responsive receptor (4αβ). The cells would be delivered through an intrapleural catheter (mesothelioma) or an intraperitoneal catheter (ovarian cancer), possibly after cyclophosphamide 1.5 g/m2. Asbestos is mentioned only as background, citing another study.
• The authors' conclusion: The authors concluded that these planned clinical studies offer a pragmatic vision of how to develop a gene-modified T-cell therapy that could harm healthy tissues carrying the same target (on-target, off-tumor toxicity).
• Limitations the authors state:
  • The authors state that the greatest challenge is that the engineered cells could target ErbB receptors normally present in healthy tissues.
  • The authors state that the immune-suppressing environment these tumors create in the pleural and peritoneal cavities is a further potential obstacle to the treatment working.
  • In mesothelioma, usual care (pleurodesis) closes off the pleural space. The authors state this compromises delivery into that cavity, so the cells must be given before that procedure.
  • The cell product is released 'at risk': sterility results from samples taken on the day of administration are not known before the cells are given.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Microenvironment, Immunotherapy, Cytokine, Monoclonal Antibody, Squamous Cell Carcinoma, Ovarian Cancer, Pleural Mesothelioma.

Related studies

• Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors — A. Morello, M. Sadelain, et al. (2016)
• T cells expressing chimeric antigen receptors can cause anaphylaxis in humans — M.V. Maus, A.R. Haas, et al. (2013)
• Targeted drug delivery and penetration into solid tumors — A. Corti, F. Pastorino, et al. (2012)
• Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy — M. O'Hara, C. Stashwick, et al. (2016)
• Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies — G.L. Beatty, A.R. Haas, et al. (2014)
• Mesothelin-targeted CAR-T cell therapy for solid tumors — A. Klampatsa, V. Dimou, et al. (2021)

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