Two HLA-matched patients with mPDAC were treated with T-cells engineered with two of these KRAS G12D-specific TCRs [1].

The first had lung and liver metastases and was treated after the standard cy/flu conditioning, plus high-dose IL-2 after infusion of the TCR-T cells. The transferred T-cells expanded in the blood, and the patient showed signs of short-term tumour regression, with either some shrinkage of lesions, with others remaining stable. Also, had reduced pain, and decreased markers of cancer cells. However, they did not respond, and despite additional treatment with an anti-PD-1 and chemo, progressed and died of disease. The failure could not be attributed to loss of mKRAS, HLA LOH, defects in the IFNy pathway, or failure of the engineered T-cells to infiltrate. So, the mechanism(s) of resistance still unknown.

A second patient, who had lung metastases, was treated, but there were a number of modifications, such as reduced cyclophosphamide, no fludarabine and an added anti-IL6R mAb was given as well. This due to complications after previous TIL therapy. Also, the T-cells were manufactured differently. She experienced a durable partial response with TCR-T cells persisting long-term, though at lower levels compared to the first patient.

Looking into why therapy was more successful, one reason was due to the phenotype of the T-cells. However, after about a year, she showed slow progression of a lung lesion, which was resected. In addition, was retreated (this time with only one of the TCRs), as well as given an anti-PD-1. Dr. Tran and colleagues are continuing to investigate why treatment efficacy varies between patients, and why differences in manufacturing improve T-cell function. They are also looking into novel synthetic receptors to increase T-cell activity in the suppressive tumour microenvironment, as well as adding other immunotherapies to enhance the efficacy of TCR-T cell therapies in solid tumours.

Finally, the personalised (proof-of-concept) TCR-T trial with the US NCI still hasn't dosed the first patient. This, despite the CRADA being signed back in early Jan '17 [2].

Ref:
1 https://www.nejm.org/doi/10.1056/NEJMoa1609279
2 https://www.bloomberg.com/press-releases/2017-01-10/ziopharm-and-intrexon-announce-cooperative-research-and
-development-agreement-with-the-national-cancer-institute-utilizing