Vaccination in gastrointestinal cancer

Sammanfattning: Advances in immunology have increased the possibility to develop therapeutic cancer vaccines (TCV), as a complementary approach to standard treatment. The goal of a successful cancer vaccine is to induce a potent long-lasting immune response against the tumour with limited toxicity on normal cells. Most tumour cells express tumour-associated antigens (TAA), which can act as targets for the immune system. However, most TAAs evade recognition by the immune system to avoid auto-immunity, as many TAAs coexist in normal tissues. Commonly expressed TAAs in gastrointestinal malignancies are Carcinoembryonic antigen (CEA) and telomerase which both have been used as targets in cancer immunotherapy. The aim of this thesis was to explore the immunogenicity and safety of a CEA based protein and DNA TCV in patients with colorectal cancer (CRC) in the adjuvant setting and telomerase vaccination (GV1001) in patients with advanced pancreatic adenocarcinoma (PC). A long-term follow-up of CRC patients immunized with recombinant (rCEA) ± Granulocyte- macrophage colony-stimulating factor (GM-CSF) was conducted. Induction of anti-CEA IgM, IgA and IgE antibodies was monitored from 36 months after start of immunization. GM-CSF significantly augmented the anti-CEA response for all three classes (p<0.05). A significant correlation between survival and high IgA anti-CEA titers was noted (p=0.02). Anti-CEA IgA antibodies could lyse CEA positive cells in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. The type, severity and duration of side-effects of CEA66-DNA vaccination in combination with cyclophosphamide and GM-CSF, was evaluated in 10 CRC patients. CEA66-DNA was delivered by a needle-free device system (Biojector). Adverse events (AE) were mild and transient, without any grade 3 or 4 AEs. No clinical signs of autoimmunity were seen. In an explorative study using CEA66-DNA (producing unglycosylated CEA) and wild type (tetwt)- CEADNA (producing glycosylated CEA) for immunization in combination with cyclophosphamide and GM-CSF immune responses (proliferation assay, ELISPOT, cytokine secretion assay) were analyzed in the adjuvant setting of CRC patients. 10 patients received intradermal (i.d.) or intramuscular (i.m.) CEA66-DNA by Biojector at weeks 0, 2 and 6 (part 1). 10 patients; (part 2), received tetwt-CEADNA 400 μg i.d. by needle followed by electroporation at weeks 0 and 12. Part 3 (n=6) included patients primed with CEA66-DNA and boosted with tetwt-CEADNA. GM-CSF and cyclophosphamide was also included. In total, 16 out of 20 (80%) patients mounted a single assay cellular response; 10/10 (100%) in part 1 and in 6/10 (60%) of the patients in part 2 (p=0.025). Immune responses were weak but durable. We also assessed the safety and immunogenicity in advanced PC patients using a 16 aa telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules (groups A, B, C) were used. In groups A and B, differing only in the dose of GM-CSF, a total of 67% of the patients showed an induced telomerase response. An induced ras (antigenic spreading) specific immune response was noted. All responses were weak and transient. A significant decrease in regulatory T cells over time was noted in patients in groups A and B. In conclusion, durable weak anti-CEA immune responses were seen following rCEA and CEA- DNA vaccination in CRC patients in the adjuvant setting. Weak and transient anti-telomerase responses following peptide vaccination were induced in patients with advanced PC. To develope a therapeutic concept of clinical significance measures have to be taken to optimize vaccine strategies.