Vaccination in gastrointestinal cancer

<p>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.</p><p>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).</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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 develop a therapeutic concept of clinical significance measures have to be taken to optimize vaccine strategies.</p><h3>List of scientific papers</h3><p>I. Staff C, Magnusson CGM, Hojjat-Farsangi M, Mosolits S, Liljefors M, Frödin JE, Wahrén B, Mellstedt H, Ullenhag G J. Induction of IgM, IgA and IgE antibodies in colorectal cancer patients vaccinated with a recombinant CEA protein. J Clin Immunol. 2012, 32:855-65. <br><a href="https://doi.org/10.1007/s10875-012-9662-7">https://doi.org/10.1007/s10875-012-9662-7</a><br><br> </p><p>II. Staff C, Mozaffari F, Haller K, Wahren B, Liljefors M. A phase I safety study of DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients. Vaccine. 2011, 29:6817-22. <br><a href="https://doi.org/10.1016/j.vaccine.2010.12.063">https://doi.org/10.1016/j.vaccine.2010.12.063</a><br><br> </p><p>III. Staff C, Mozaffari F, Haller KB, Frödin JE, Wahren B, Mellstedt H, Liljefors M. DNA immunization targeting carcinoembrynic antigen in colorectal cancer patients. [Manuscript]</p><p>IV. Staff C, Mozaffari F, Frödin JE, Mellstedt H, Liljefors M. Telomerase-peptide vaccination (GV1001) together with gemcitabine in advanced pancreatic cancer patients. [Manuscript]</p>