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Reassessing target antigens for adoptive T-cell therapy
Christian S Hinrichs1, Nicholas P Restifo
1National Cancer Institute, Surgery Branch, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Adoptive T-cell therapy can target and kill widespread malignant cells thereby inducing durable clinical responses in melanoma and selected other malignances. However, many commonly targeted tumor antigens are also expressed by healthy tissues, and T cells do not distinguish between benign and malignant tissues if both express the target antigen. Autoimmune toxicity from T cell-mediated destruction of normal tissue has limited the development and adoption of this otherwise promising type of cancer therapy. A review of the unique biology of T-cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities. It is important that target antigens chosen for adoptive T-cell therapy are expressed by tumors and not by essential healthy tissues. The risk of adverse autoimmune events can be further mitigated by generating antigen receptors using strategies that reduce the chance of cross-reactivity against epitopes in unintended targets. In general, a circumspect approach to target selection and thoughtful preclinical and clinical studies are pivotal to the ongoing advancement of these promising treatments.
Insights
Adoptive T-cell therapy shows promise for cancer treatment but can cause autoimmune side effects. Careful selection of tumor antigens, avoiding those on healthy tissues, is crucial for safer, more effective therapies.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Adoptive T-cell therapy effectively targets malignant cells, offering durable responses in cancers like melanoma.
- A significant challenge is autoimmune toxicity due to T cells attacking healthy tissues expressing shared antigens.
- This limits the broader application of T-cell therapies.
Purpose of the Study:
- To reassess target antigen selection for adoptive T-cell therapy.
- To mitigate autoimmune toxicity by identifying tumor-specific antigens.
- To guide the development of safer and more effective T-cell treatments.
Main Methods:
- Review of T-cell therapy biology and clinical data.
- Analysis of tumor antigen expression profiles in malignant and healthy tissues.
- Evaluation of strategies to minimize T-cell receptor cross-reactivity.
Main Results:
- Many current tumor antigens are also present in essential healthy tissues, leading to autoimmune risks.
- Target antigens must be selectively expressed by tumors, not vital normal tissues.
- Strategies to reduce cross-reactivity can further mitigate adverse autoimmune events.
Conclusions:
- Circumspect target antigen selection is paramount for safe and effective adoptive T-cell therapy.
- Thoughtful preclinical and clinical studies are essential for advancing this treatment modality.
- Prioritizing tumor-specific antigens will improve the therapeutic index of T-cell therapies.
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