Engineered Cellular Therapies for the Treatment of Thoracic Cancers

Our plain-English summary of Engineered Cellular Therapies for the Treatment of Thoracic Cancers, by S.M. Erickson, B.M. Manning, A. Kumar, et al (Cancers, 2024).

The study

• Authors: S.M. Erickson, B.M. Manning, A. Kumar, M.R. Patel
• Journal: Cancers
• Published: 2024;17(1)
• Type of article: Review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Thoracic malignancies (lung cancers and malignant pleural mesothelioma) are prevalent worldwide and are associated with high morbidity and mortality. Effective treatments are needed for patients with advanced disease. Cell therapies are a promising approach to the treatment of advanced cancers that make use of immune effector cells that have the ability to mediate antitumor immune responses. In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies. CAR-T cells and TILs have proven successful in several hematologic cancers and advanced melanoma, respectively, but outside of melanoma, results have thus far been unsuccessful in most other solid tumors. NK cells and TCR-T cells are additional cell therapy platforms with their own unique advantages and challenges. Obstacles that must be overcome to develop effective cell therapy for these malignancies include selecting an appropriate target antigen, combating immunosuppressive cells and signaling molecules present in the tumor microenvironment, persistence, and delivering a sufficient quantity of antitumor immune cells to the tumor. Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles.

In plain English

This was a narrative review of engineered cell therapies for thoracic cancers: lung cancers and malignant pleural mesothelioma (MPM). The authors surveyed chimeric antigen receptor T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells and tumour-infiltrating lymphocytes (TILs), covering target antigens, cell sources, published trials and ongoing registered trials (last searched 10 July 2024). Among trials they summarised: in a randomised TIL trial, patients with stage 3b non-small cell lung cancer had median overall survival of 23.9 months with TILs plus radiotherapy versus 7.3 months with chemotherapy plus radiotherapy (p less than 0.01); a phase 2 TIL trial reported an objective response rate of 21.4% (95% CI, 8.3-41.0) in 28 patients; in an MPM cohort given intrapleural mesothelin-targeted CAR-T followed by pembrolizumab, 2 of 16 patients with measurable disease had partial responses; and the mesothelin-directed product gavo-cel produced objective responses in 20% (6/30) of patients with various solid tumours including MPM, with cytokine release syndrome in 78%. The authors concluded CAR-T cells have yet to show impressive efficacy in thoracic malignancies and that safety concerns remain.

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: narrative review of clinical trials and preclinical research on cell therapies for thoracic cancers
• Who was studied: Published clinical trials of cell therapies in patients with lung cancer or malignant pleural mesothelioma, plus preclinical studies and actively recruiting trials registered on clinicaltrials.gov (last searched 10 July 2024)
• Exposure: Not an exposure study; the treatments reviewed were CAR-T cells, NK cells, TCR-T cells and TILs, with target antigens such as mesothelin, EGFR, ROR1, DLL3, MUC1, MAGE-A4 and MAGE-A10
• Main results:
  • In the randomised TIL trial reviewed (Ratto 1996), patients with stage 3a or 3b disease were randomised to TILs plus radiotherapy or to radiotherapy plus chemotherapy
  • In that trial, patients with stage 3b disease had median overall survival of 23.9 months with TILs plus radiotherapy versus 7.3 months in the control group (chemotherapy plus radiotherapy)
  • In the phase 2 TIL trial reviewed (Schoenfeld 2024) in metastatic NSCLC after anti-PD-1/PD-L1 therapy, 19 of 28 infused patients had reduced tumour burden and the objective response rate was 21.4%
  • In the phase 1 TIL trial reviewed (Creelan 2021) in metastatic NSCLC, 3 of 13 evaluable patients had a confirmed response
  • The intrapleural mesothelin-targeted CAR-T trial reviewed (Adusumilli 2021) included a cohort of 18 MPM patients given pembrolizumab 4 weeks after CAR-T injection
  • In that MPM plus pembrolizumab cohort, 2 of 16 patients with measurable disease achieved a partial response and 5 of 16 had progressive disease
  • Median overall survival from CAR-T infusion among those patients was 23.9 months and 1-year overall survival 83%
  • For the mesothelin-targeted TRuC T cell product gavo-cel reviewed (Hassan 2023), objective responses occurred in 20% (6/30) of patients across solid tumour types, one of whom had MPM
  • Cytokine release syndrome occurred in 78% of patients in the gavo-cel study
  • In the NK cell trial reviewed (Multhoff 2020) in unresectable NSCLC, the 1-year probability of progression-free survival was 67% with NK cells versus 33% in controls, which was not statistically significant
• The authors' conclusion: The authors concluded that CAR-T cells have not yet shown impressive efficacy in thoracic malignancies and that safety concerns remain. Because only phase 1 trials have reported results, they said little can yet be said about their efficacy. They considered cell therapies promising but said much more basic research is still needed.
• Limitations the authors state:
  • The authors stated that differences between trials make direct efficacy comparisons difficult
  • The authors stated that older and newer TIL trials are hard to compare because recent trials enrolled more heavily pretreated patients with more advanced disease
  • The authors stated that many strategies they describe come from preclinical studies and are not close to human testing
  • The authors stated that detailed CAR design and engineering were outside the scope of the review

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Pleural Mesothelioma, Tumor-Infiltrating Lymphocytes, CAR-T Cell, Tumor Microenvironment, STEM, Clinical Trial.

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• Malignant pleural mesothelioma: update on treatment options with a focus on novel therapies — A.R. Haas, D.H. Sterman (2013)
• A systematic review and meta-analysis of second-line therapies for treatment of mesothelioma — F. Petrelli, R. Ardito, et al. (2018)
• Phytochemicals in Malignant Pleural Mesothelioma Treatment-Review on the Current Trends of Therapies — M. Chmielewska-Kassassir, L.A. Wozniak (2021)
• Emerging biological therapies for the treatment of malignant pleural mesothelioma — A.P. Davis, S.C. Kao, et al. (2021)
• Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study — A. Mathilakathu, S. Borchert, et al. (2021)

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