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Treatment with IMM-101 induces protective CD8+ T cell responses in clinically relevant models of pancreatic cancer
© Elia et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Pancreatic cancer is an aggressive cancer with poor prognosis. Despite its low incidence, it is the 4th cause of cancer-related death in the US. Treatment options have only marginally improved on survival rates, which have remained low, with about 25% survival at 12 months and 5% at 5 years. For these reasons, new therapeutic strategies are urgently needed including immunotherapeutic approaches. We have investigated the immunotherapeutic effect of IMM-101, a heat-killed whole cell preparation of Mycobacterium obuense currently undergoing investigation in a Phase II clinical trial in pancreatic cancer (EudraCT n. 2010-022757-42), in two clinically relevant murine models of pancreatic cancer, which histologically mirror human pancreatic adenocarcinomas. Genetically-modified mice bearing mutations in Kras, p53 and Pdx-Cre (KPC mice) were treated with IMM-101 immediately after development of a palpable tumour. Whereas IMM-101 treatment was unable to effect survival in this rather aggressive model, it did, however, significant decrease metastatic burden. Moreover, it appeared to expand a population of antigen experienced CD8+ T cells bearing CD45RBlowCD44high and able to produce IFN-γ and perforin. On the basis of these promising observations, we explored further whether treatment with IMM-101 could induce cytotoxic CD8+ T cells able to effect disease outcome. We treated mice bearing mutations in Kras and Pdx-Cre (KC mice) with IMM-101 and found that not only was survival significantly increased, but also that IMM-101 treatment altered their immune response to disease. We observed systemic T cell activation at the tumour site, the draining lymph nodes and the spleen, as measured by CD69 expression on T cells. More importantly, in mice treated with IMM-101, CD8+ T cells were found in higher numbers compared to untreated mice, in both the draining lymph nodes and at the tumour site. These CD8+ T cells were characterized by increased production of IFN-γ, perforin and granzyme, identifying them as cytotoxic CD8+ effector T cells. To further confirm that the mode of action of IMM-101 was directly depended on CD8+ T cells, we depleted these cells in treated mice with a neutralizing antibody. We found that depletion of CD8+ T cells, but not for example depletion of NK cells, was responsible for the loss of therapeutic effect. We are currently sequencing the CD8+ T cell TCR to determine specificity. We propose that treatment with IMM-101 is able to induce CD8+ T cell-dependent protective effects in the host and limit disease progression. We expect that in combination therapies these immunotherapeutic effects may be further increased.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.