Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 TCR engineered T cells. Five patients experienced clinical regression of their cancers including two on-going responders. Beginning 1–2 days post-infusion, three patients (#’s 5, 7, and 8) experienced mental status changes, and two patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3+/CD8+ T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using Q-RT-PCR, Nano string quantitation, and deep-sequencing indicated that MAGE -A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.

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Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These “cancer stem cells” (CSCs) present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer.

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Background Colorectal cancer (CRC) progression is mediated by cancer stem cells (CSCs). We sought to determine if expression of the CSC marker aldehyde dehydrogenase 1 (ALDH1) in CRC tumors varies by AJCC stage or correlates to clinical outcomes. Methods Primary and metastatic CRC samples from 96 patients were immunostained with antibodies to ALDH1 and imaged to evaluate marker expression. The percentage of ALDH1+ cells was correlated to clinical outcomes. Results ALDH1 was overexpressed in CRC tumors compared to non-neoplastic tissue. Marker expression was highest in non-metastatic tumors; loss of expression was associated with advanced stage and metastatic disease. No significant correlation was found between ALDH1 expression and metastasis, recurrence or survival. Conclusions ALDH1 was highly expressed in non-metastatic CRC, but expression was lost with advancing stage. ALDH1 could be an effective therapeutic target in early CRC but not late stage disease. No correlation was found between ALDH1 and disease prognosis.