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.

In female patients with MEN1, estrogen exposure may inhibit PNET growth. A demonstrable protective effect against PNET tumourigenesis, tumour growth and survival of patients with these tumours may require a larger cohort.

No abstract

e18083 Background: The value of sequencing cell-free DNA (cfDNA) from patients with papillary carcinoma of the thyroid (PTC) is controversial. Studies utilizing whole-exome sequencing (WES) or single-gene detection methods have reported lower mutational yield in cfDNA in PTC compared with other cancers. Alternatively, mutational analyses of anaplastic thyroid carcinoma (ATC), which is thought to evolve from PTC, demonstrate high levels of mutated cfDNA. We report on mutations in tumor and cfDNA at initial surgery for PTC, correlate with clinicopathologic status and further characterize the mutational landscape of these tumors in tissue and blood utilizing deep-sequencing panel testing. Methods: 50 patients were enrolled 2017-2020. Tempus xT (648 genes) and xF (105 genes) panels were used to prepare next generation sequencing libraries from tissue and blood samples, respectively. Cell-free DNA (cfDNA) sequencing depth average is 20,000x (raw reads)/5,000x (unique reads). Results: More than half of the patients had pT3-T4 tumors and/or local metastases and one had distant metastasis. 47/47 (100%) of processable tissue samples and 40/49 (81.6%) of blood samples yielded at least one relevant mutation. BRAF V600E was found in 77% of tissue and 8% of cfDNA, while mutated TERT was detected in 17% of tissue and none of the blood samples. The most frequently mutated genes in cfDNA were KMT2A (18% of blood samples, 6 % tissue), ATM (12% blood, 6% tissue), and TP53 (12% blood, 2 % tissue). There was marked mutational heterogeneity among samples, and a range of alterations representing multiple oncogenic pathways. Conclusions: Patients at initial surgery demonstrated highly mutated tissue DNA, including BRAF, TERT and other mutations known to be found in PTC. The most frequent tissue mutations were found at higher rates than previously reported by WES, which may reflect the sensitivity of targeted deep sequencing versus WES, and possibly a selection bias of more advanced PTC. A high percentage of cfDNA samples yielded mutations relevant to thyroid cancer, and the absence of TERT is consistent with prior studies. Mutations and co-mutations associated with de-differentiation and worse outcomes were demonstrated in both tissue and cfDNA. Interestingly, mutations more common in ATC than PTC, such as TP53, were detected in cfDNA, often without primary tumor correlate. Since mutations associated with aggressive behavior may be found in metastatic foci while not detected in the primary tumor, we conclude that cfDNA may reveal prognostic information important for the development of surveillance strategies in selected patients with residual PTC after surgery who may be at risk for poor outcomes.