Final Report Summary - TIPC_TIL_IP (T-cell based immunotherapy in pancreatic cancer - basic concepts and pre-clinical development)
Pancreatic ductal adenocarcinoma (PDA) is the most prevalent type of pancreatic cancer. Due to lack of symptoms in early disease stages, most patients present with locally advanced or metastatic tumors. This patient group can only be offered palliative care and faces a devastating mean survival of <6 months. Only 20% of patients presenting with PDA are eligible for surgical tumor resection and their disease almost inevitably recurs, highlighting the need for new treatment strategies.
Adoptive transfer of in vitro expanded tumor infiltrating lymphocytes (TIL) has recently emerged as a potent strategy for treating and even curing advanced cancer, with particular success in patients with melanoma. Although PDA has been branded as poorly immunogenic, we found immune cell infiltrates, including T-cells, in a majority of PDA specimens. We can successfully expand TIL, which strongly resemble melanoma TIL, from >80% of patients with resectable PDA, and aim to develop T-cell based therapies as a treatment option for PDA.
Based on our findings the two following objectives were defined for the TIPC-TIL-project:
I. To obtain pre-clinical proof of concept for TIL therapy in PDA that will enable first-in-human studies
II. To perform an in depth characterization of the nature and specificity of the TIL-response observed in PDA
The key results of our project can be summarized as follows:
T-cell receptor (TCR) sequencing shows that the TIL repertoire is distinct from that of circulating T-cells, with certain TCR sequences being up to 10.000-fold enriched in the tumor as compared to blood, pointing towards intra-tumoral accumulation of tumor-reactive cells. In line with this, we observed so-called tertiary lymphoid structures (TLS) in many of the tumor biopsies examined and found that the presence of these TLS constitutes a positive prognostic factor for post-surgery patient survival. Moreover, the vast majority of expanded PDA TIL was shown to display MHC-restricted reactivity against the tumor they were derived from. Investigations into the antigens recognized by PDA TIL, with a particular focus on epitopes derived from somatic mutations, are ongoing. PDA TIL express markers of activation and antigen encounter that will be useful for identifying tumor-reactive T-cells or TCRs directly ex vivo. Based on our findings, we are working towards an optimized protocol for the isolation, ex vivo expansion and clinical application of PDA TIL to counter the devastating recurrence rate in patients with primary resectable PDA.
During the funding period, Dr. Poschke, strongly supported by department head Prof. Offringa, has become a well-established expert on T-cell-based immunotherapy on the Heidelberg medical campus. She is viewed as an independent researcher and contributes to the research community by organizing seminars, reviewing papers and chairing sessions at intramural and international scientific conferences. She is involved in various teaching activities and the supervision of graduate and under-graduate students. The described data has resulted in one publication and additional manuscripts are in preparation. Dr. Poschke was also selected to present at scientific meetings and seminars, which allowed her to maintain and expand her network with researches in the field. As intended, the career-integration grant enabled Dr. Poschke to perform innovative research, which formed the basis to successfully apply for additional funding.
Adoptive transfer of in vitro expanded tumor infiltrating lymphocytes (TIL) has recently emerged as a potent strategy for treating and even curing advanced cancer, with particular success in patients with melanoma. Although PDA has been branded as poorly immunogenic, we found immune cell infiltrates, including T-cells, in a majority of PDA specimens. We can successfully expand TIL, which strongly resemble melanoma TIL, from >80% of patients with resectable PDA, and aim to develop T-cell based therapies as a treatment option for PDA.
Based on our findings the two following objectives were defined for the TIPC-TIL-project:
I. To obtain pre-clinical proof of concept for TIL therapy in PDA that will enable first-in-human studies
II. To perform an in depth characterization of the nature and specificity of the TIL-response observed in PDA
The key results of our project can be summarized as follows:
T-cell receptor (TCR) sequencing shows that the TIL repertoire is distinct from that of circulating T-cells, with certain TCR sequences being up to 10.000-fold enriched in the tumor as compared to blood, pointing towards intra-tumoral accumulation of tumor-reactive cells. In line with this, we observed so-called tertiary lymphoid structures (TLS) in many of the tumor biopsies examined and found that the presence of these TLS constitutes a positive prognostic factor for post-surgery patient survival. Moreover, the vast majority of expanded PDA TIL was shown to display MHC-restricted reactivity against the tumor they were derived from. Investigations into the antigens recognized by PDA TIL, with a particular focus on epitopes derived from somatic mutations, are ongoing. PDA TIL express markers of activation and antigen encounter that will be useful for identifying tumor-reactive T-cells or TCRs directly ex vivo. Based on our findings, we are working towards an optimized protocol for the isolation, ex vivo expansion and clinical application of PDA TIL to counter the devastating recurrence rate in patients with primary resectable PDA.
During the funding period, Dr. Poschke, strongly supported by department head Prof. Offringa, has become a well-established expert on T-cell-based immunotherapy on the Heidelberg medical campus. She is viewed as an independent researcher and contributes to the research community by organizing seminars, reviewing papers and chairing sessions at intramural and international scientific conferences. She is involved in various teaching activities and the supervision of graduate and under-graduate students. The described data has resulted in one publication and additional manuscripts are in preparation. Dr. Poschke was also selected to present at scientific meetings and seminars, which allowed her to maintain and expand her network with researches in the field. As intended, the career-integration grant enabled Dr. Poschke to perform innovative research, which formed the basis to successfully apply for additional funding.