22 research outputs found
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Investigating the potential of the Metastasis Associated Antigen 1 (MTA1) for cancer immunotherapy in a murine model
No full textImmunotherapeutic approaches to target antigens associated with metastasis could provide a valuable means of targeting metastatic cells specifically. Metastasis Associated Antigen (MTA1) is one such relatively novel antigen, which has been associated with aggressive tumours, and shown to be over expressed in breast, oesophageal, colorectal, gastric and pancreatic cancer, amongst others. Various studies have indicated that MTA1 is essential for the transformation of cells and hence targeting it is unlikely to generate antigen loss variants. This study proposed to investigate MTA1 as a potential target for immunotherapy in a murine tumour model. We have shown that murine MTA1 (mMTA1) mRNA is highly expressed in most of the tumour cell lines as compared to normal tissues, which express mMTA1 at very low levels. Furthermore, to rule out any post-transcriptional modifications, MTA1 protein levels were also confirmed by western blotting. It was observed that most of the cell lines expressed MTA1 at high levels, whereas no protein expression was detected in the normal tissues by western blotting. Next, we decided to identify MHC class I and II restricted immunogenic peptides from murine and human MTA1 gene for syngeneic and transgenic mice respectively
Exploiting evolution to treat drug resistance: Combination therapy and the double bind
No full textAlthough many anti cancer therapies are successful in killing a large percentage of tumour cells when initially administered, the evolutionary dynamics underpinning tumour progression mean that often resistance is an inevitable outcome, allowing for new tumour phenotypes to emerge that are unhindered by the therapy. Research in the field of ecology suggests that an evolutionary double bind could be an effective way to treat tumours. In an evolutionary double bind two therapies are used in combination such that evolving resistance to one leaves individuals more susceptible to the other. In this paper we present a general evolutionary game theory model of a double bind to study the effect that such approach would have in cancer. Furthermore we use this mathematical framework to understand recent experimental results that suggest a synergistic effect between a p53 cancer vaccine and chemotherapy. Our model recapitulates the experimental data and provides an explanation for its effectiveness based on the commensalistic relationship between the tumour phenotypes
Vaccination strategies for malignant diseases Deepak P Assudani, Stephanie McArdle, Murrium Ahmad, Geng Li, Robert C Rees, Selman A Ali
No full textSuccessful administration of BI 695501, an adalimumab biosimilar, using an autoinjector (AI): results from a Phase II open-label clinical study (VOLTAIRE<sup>®</sup>-RL)
No full textAbstract 5599: Novel mechanism of synergistic effect of cancer immunotherapy and chemotherapy
No full textAbstract
Despite advances in the development of new chemotherapeutic drugs and improvements in radiation therapy, conventional cancer therapy often falls short of the goal of controlling tumor progression. Emerging clinical and pre-clinical evidence suggests that an immune response elicited by using vaccines augments the anti-tumor effectiveness of subsequent chemotherapy. The main objectives of this study are to determine if combining vaccines with chemotherapeutic agents would render tumor cells more susceptible to T cell mediated killing and to identify the mechanisms involved.
In this study we used three drugs with different mechanisms of action- Paclitaxel (TAX), Doxorubicin (DOX) and Cisplatin (CIS). Using Cr51 release assays, we found that all three agents, at very low doses, accelerated killing of antigen specific tumor cells by Cytotoxic T lymphocytes (CTLs). This effect was observed with CTLs specific to different antigens.
Perforin-granzyme and Fas-FasL pathways are two major mechanisms by which CTLs destroy target cells. All three drugs did not affect the expression of either Fas or FasL on tumor cells but caused dramatic increase in permeability of cell membrane to granzyme B (GrB). Receptor studies revealed that TAX, DOX, and CIS induced substantial increase in the expression of mannose-6-phosphate receptor (MPR) on human and mouse tumor cells, but not in normal cells. MPR is considered an important factor that together with perforin mediates GrB entry into the cell.
Using CTLs from normal (WT) and Perforin Knockout (PKO) mice, we evaluated the levels of CTL mediated killing in chemotherapy treated, antigen specific tumor cells. Simultaneously, we examined CTL mediated killing after blocking MPR receptors on tumor cells. Our data demonstrated that chemotherapy regulates GrB uptake via up-regulation of MPR and bypasses the requirement for perforin. Adoptive transfer of T cells from WT and PKO mice, in tumor models, followed by chemotherapy confirmed the efficacy of combination therapy in delaying tumor growth, independent of perforin.
Our data suggests a mechanism for the combined effect of CTLs and chemotherapy. Chemotherapy, administered immediately after vaccination or T-cell transfer, causes disruption of tumor stroma that allows for better penetration of antigen-specific T cells. In addition, chemotherapy causes substantial increase in MPR expression on tumor cells. Small number of activated CTLs interacting with tumor cells expressing tumor antigen, release GrB that can penetrate into neighboring tumor cells without requirement for perforin, initiating localized bystander killing. Thus large number of tumor cells including those that do not express specific antigen would be susceptible to the effect of CTLs.
This provides a rationale for treatment of advanced stage cancer patients by combining standard of care chemotherapy with relatively non-toxic and highly specific immunotherapy
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5599.</jats:p
Immunotherapeutical potential of DISC-HSV and OX40L in cancer
No full textSeveral vectors, viral and bacterial, have been developed over the past few years for means of generating an effective anti-tumor immune response. We have developed and studied a “model for immunotherapy” using a viral vector DISC-HSV, which efficiently transduces various tumor cell lines and offers a useful vehicle for the further development of cell based vaccines. The immunotherapeutic potential of DISC-HSV encoding GMCSF was demonstrated in a number of murine carcinoma models, leading to complete regression of well established tumors in up to 70% of the mice. Moreover, the therapeutic potential of DISC-HSV-GMCSF was significantly enhanced when used in combination therapy with either OX40L or dendritic cells (DC), even in poorly immunogenic tumor model. The ability of this vector to accept large gene inserts, its good safety profile, its ability to undergo only a single round of infection, the inherent viral immunostimulatory properties and its ability to infect various tumor cell lines efficiently, make DISC-HSV an ideal candidate vector for immunotherapy. The DISC- CT-26 tumor model has been used to investigate these mechanisms associated with immunotherapy – induced tumor rejection. Although CTL induction, was positively correlated with regression, MHC class I down regulation and accumulation of immature Gr1+ myeloid cells were shown to be the main immuno-suppressor mechanisms operating against regression and associated with progressive tumor growth
Immunological persistence in 5 y olds previously vaccinated with hexavalent DTPa-HBV-IPV/Hib at 3, 5, and 11 months of age
No full textThe combined diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis/Haemophilus influenza vaccine (DTPa-HBV-IPV/Hib: Infanrix hexa, GlaxoSmithKline Vaccines) is used for primary vaccination of infants in a range of schedules world-wide. Antibody persistence after 4 DTPa-HBV-IPV/Hib doses in the first 2 y of life has been documented, but long-term persistence data following the 3, 5, 11-12 months (3-5-11) infant vaccination schedule, employed for example in Nordic countries, are limited. We assessed antibody persistence in 57 5-year-old children who had received either DTPa-HBV-IPV/Hib or DTPa-IPV/Hib (Infanrix-IPV/Hib, GlaxoSmithKline Vaccines) in the 3-5-11 schedule. Among DTPa-HBV-IPV/Hib recipients, 7/12 retained seroprotective antibody concentrations for diphtheria, 10/12 for tetanus, 5/12 for hepatitis and 10/12 for Hib. Detectable antibodies were observed for 0/12 children for pertussis toxin (PT), 12/12 for filamentous haemagglutinin (FHA) and 8/12 for pertactin (PRN). Among DTPa-IPV/Hib recipients, 28/45 retained seroprotective anti-diphtheria concentrations, 34/44 for tetanus and 40/45 for Hib. Detectable antibodies were observed for 9/45 children for PT, 41/45 for FHA and 34/45 for PRN. Antibody persistence in DTPa-HBV-IPV/Hib and DTPa-IPV/Hib-vaccinees appeared similar in 5 y olds to that previously observed in children of a similar age who had received 4 prior doses of DTPa-HBV-IPV/Hib (or DTPa-IPV/Hib). As in subjects primed with 4 prior doses, we observed that antibodies markedly declined by 5 y of age, calling for the administration of a pre-school booster dose in order to ensure continued protection against pertussis
The role of CD4+ T cell help in cancer immunity and the formulation of novel cancer vaccines
No full textChemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice
No full textImmunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV-IPV/Hib vaccine in Canadian Aboriginal and non-Aboriginal infants
No full textAbstractThis study compared immune responses of healthy Aboriginal and non-Aboriginal infants to Haemophilus influenzae type b (Hib) and hepatitis B virus (HBV) components of a DTaP-HBV-IPV/Hib combination vaccine, 1 month after completing dosing at 2, 4 and 6 months of age. Of 112 infants enrolled in each group, 94 Aboriginal and 107 non-Aboriginal infants qualified for the immunogenicity analysis. Anti-PRP concentrations exceeded the protective minimum (≥0.15μg/ml) in ≥97% of infants in both groups but geometric mean concentrations (GMCs) were higher in Aboriginal infants (6.12μg/ml versus 3.51μg/ml). All subjects were seroprotected (anti-HBs ≥10mIU/mL) against HBV, with groups having similar GMCs (1797.9 versus 1544.4mIU/mL, Aboriginal versus non-Aboriginal, respectively). No safety concerns were identified. We conclude that 3-dose primary vaccination with DTaP-HBV-IPV/Hib combination vaccine elicited immune responses to Hib and HBV components that were at least as high in Aboriginal as in non-Aboriginal Canadian infants.Clinical Trial Registration NCT00753649
