Dr Sebastian Kobold, University Hospital of Munich (LMU); Prof. Stefan Endres, University Hospital of Munich (LMU); Moritz Rapp, University Hospital of Munich (LMU); Simon Grassmann, University Hospital of Munich (LMU)
Adoptive T cell therapy (ACT) is a powerful approach to treat even advanced stages of cancer. ACT utilizing so called chimeric antigen receptors (CAR) have been approved for the treatment of refractory acute lymphatic leukemia and diffuse large B cell lymphoma by the FDA. In other non-hematologic cancer indications the successes of ACT are much more limited. A major hurdle encountered in this setting where tumor cells are surrounded by a dense impenetrable stroma, is the access or infiltration of the transferred T cells to the tumor site. As a contact between the T cell and the tumor cell is a prerequisite for therapeutic T cell action, it is unsurprising that T cell infiltration in a given tumor has been identified as a major predictor of response to T cell based therapies. Enabling access of ACT to the tumor tissue is of major importance for treatment response. Currently available strategies do not address this issue specifically and therefore only lead to modest treatment responses.
We have identified the C-X-C-motif receptor 6 (CXCR6) as a chemokine receptor, which is not naturally expressed by cytotoxic T cells but only by a subset of CD4+ T cells. In contrast its only known ligand CXCL16 is highly expressed by a number of different entities, including pancreatic, lung and breast cancer. CXCL16 is expressed on both the cancer cells themselves and their surroundings, providing an opportunity for enhanced attraction of CXCR6-positive cells. We have thus engineered antigen specific T cells (TCR and CAR) with CXCR6 for enhanced attraction of these T cells to the tumor site following a CXCL16 gradient. We found strong migration of T cells to the tumor tissue leading to tumor rejection in most animal models (syngeneic and xenograft models) we have tested. We thus provide an approach arming antigen-specific T cells with a chemokine receptor that matches a chemokine gradient present in a number of different cancer entities for ACT enablement.
The target market for the product is the treatment of patients suffering from metastatic or locally advanced pancreatic carcinoma.
The global market for cancer drugs in 2014 amounted to 89 billion euros (Forbes Magazine). The indication for pancreatic carcinoma is 529 million euros for the US and Europe alone. Thus, the indication of pancreatic carcinoma occupies a leading position in the sales of cancer therapeutics. 80% of patients are diagnosed with advanced-stage pancreatic cancer.
Every year 100,000 patients in the US and Europe are diagnosed with pancreatic carcinoma (incidence) for the first time. The mortality of pancreatic carcinoma corresponds approximately to its incidence. The annual incidence is expected to increase by 20% over the next decade (globaldata). Almost all patients require systemic therapy for advanced disease at some point in their illness. The basis for the application of our therapy concept is the generation of an autologous cell product derived from the patient´s cells. It is estimated that about one-third of patients with advanced pancreatic carcinoma would be eligible for the therapy described. Based on current figures in this area, this would correspond to a market volume of 176 million euro per year.
We have generated PoC and PoP data both in vitro and in vivo in syngeneic and human tumor models of pancreatic cancer using TCR and CAR-based approaches. We are currently validating the value of the technology in different tumor entities utilizing alternative CARs.
PCT patent application filed in 2016