Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Chantale Bernatchez and Patrick Hwu
Carlos Antonio Torres-Cabala
The success of checkpoint blockade immunotherapy (CBI) has reinvigorated the cancer therapy field, particularly for advanced melanoma which has doubled the survival rates compared to 20 years ago. However, there are many solid tumor types that are yet to receive substantial benefit from this groundbreaking therapy, two of which are pancreatic cancer (PDAC) and ovarian cancer (OvCa). As such, the 5-year survival rate for PDAC and OvCa stand at 9% and 28% respectively. Despite the lack of efficacy of CBI so far, there is still evidence for the role of immune control in these cancers as evidenced by presence of tumor-infiltrating lymphocytes (TIL) correlating with increased survival. Since in vivo manipulation of TIL through CBI does not seem to be sufficient to generate a strong clinical response, approaches involving ex vivo manipulation of immune cells, such as adoptive cell therapy (ACT) using autologous TIL, might be able to provide therapeutic benefit. The effectiveness of TIL ACT has been demonstrated in metastatic melanoma with overall response rates around 50%. Given this success and the anti-tumor potential of the immune infiltrate in PDAC and OvCa, I sought to assess the feasibility of TIL ACT in these solid tumors. My work here has demonstrated the feasibility of TIL ACT for PDAC and OvCa by showing that they harbor an activated, anti-tumor CD8+ T-cell infiltrate that can be robustly and reliably expanded using an improved 3-signal culture method consisting of a CD3 stimulation, an agonistic 4-1BB mAb, and high-dose IL-2. Additionally, these results show that TIL ACT for PDAC and OvCa is viable regardless of primary or metastatic site and regardless of prior chemotherapy. Furthermore, given the difficulty of treating PDAC, single-cell RNA sequencing was used to interrogate the immune landscape to further our understanding of the TIL heterogeneity in PDAC. Paired transcriptomic and T-cell receptor sequencing revealed novel TIL populations with potential prognostic and therapeutic implications. A Phase II clinical trial based on this work has been initiated at MDACC to evaluate the feasibility of the adoptive transfer of autologous TIL in recurrent or refractory PDAC and OvCa (NCT03610490).
TUMOR-INFILTRATING LYMPHOCYTES, ADOPTIVE CELL THERAPY, TIL THERAPY, PANCREATIC CANCER, OVARIAN CANCER, SINGLE-CELL RNA SEQUENCING