A phase I trial in melanoma patients using dendritic cells pulsed with a novel synthetic iNKT cell agonist
Lead Research Organisation:
University of Oxford
Department Name: Nuffield Dept of Clinical Medicine
Abstract
Tumour immunology is now on a very solid and conceptual footing. The challenge remains to translate these results into the clinic. There is a great expectation that cancer vaccines will offer advantages over conventional cancer treatments . Vaccines are likely to produce fewer and milder side-effects than chemotherapy and radiotherapy as they specifically target cancer cells only.
The ideal immune response to a cancer vaccine would be ?integrated , meaning that all components of the immune system, killer cells, helper cells and antibodies, are generated to target tumour cells, leading to the destruction of the cancer cells. Such integrated immune responses require that vaccination strategies facilitate an optimal cross-talk between different cells of the immune system.
Current vaccination strategies, based on the use of recombinant attenuated viruses, are failing to trigger such an integrated response, since immune responses in patients vaccinated with current vaccination protocols are orders of magnitudes weaker than those immune responses observed during natural infections. Optimizing vaccination protocols requires a deeper understanding of the signals that the immune system coordinates to respond to pathogenic infection. Compounds that mimic these signals may therefore be exploited as adjuvants in current vaccination strategies. Advances in molecular technology have permitted the design of ?subunit? vaccines directed at protein targets, providing immunotherapy with a degree of specificity that was not possible using traditional vaccines based on live attenuated viruses.
Over the last few years we have characterised a series of synthetic compounds capable of activating a population of cells, called invariant NKT cells, which orchestrate the maturation of professional antigen presenting cells (dendritic cells) resulting in the activation of killer cells, helper cells and antibody producing cells. The results of these studies have been possible through a concerted effort between immunologists, structural biologists and organic chemists.
We are now very keen to translate these results into the clinic to assess whether the results obtained in pre-clinical models can be applied to cancer patients and trigger an integrated cancer specific immune response.
The ideal immune response to a cancer vaccine would be ?integrated , meaning that all components of the immune system, killer cells, helper cells and antibodies, are generated to target tumour cells, leading to the destruction of the cancer cells. Such integrated immune responses require that vaccination strategies facilitate an optimal cross-talk between different cells of the immune system.
Current vaccination strategies, based on the use of recombinant attenuated viruses, are failing to trigger such an integrated response, since immune responses in patients vaccinated with current vaccination protocols are orders of magnitudes weaker than those immune responses observed during natural infections. Optimizing vaccination protocols requires a deeper understanding of the signals that the immune system coordinates to respond to pathogenic infection. Compounds that mimic these signals may therefore be exploited as adjuvants in current vaccination strategies. Advances in molecular technology have permitted the design of ?subunit? vaccines directed at protein targets, providing immunotherapy with a degree of specificity that was not possible using traditional vaccines based on live attenuated viruses.
Over the last few years we have characterised a series of synthetic compounds capable of activating a population of cells, called invariant NKT cells, which orchestrate the maturation of professional antigen presenting cells (dendritic cells) resulting in the activation of killer cells, helper cells and antibody producing cells. The results of these studies have been possible through a concerted effort between immunologists, structural biologists and organic chemists.
We are now very keen to translate these results into the clinic to assess whether the results obtained in pre-clinical models can be applied to cancer patients and trigger an integrated cancer specific immune response.
Technical Summary
Background: The overall aim of this research programme is to carry out a phase I clinical trial in melanoma patients to test a novel vaccination strategy bridging the adaptive and innate arms of the immune system. T cell responses to natural infection are orders of magnitude greater than those observed in patients vaccinated with current vaccination protocols. Optimizing vaccination protocols requires a deeper understanding of the signals that the immune system coordinates to respond to pathogenic infection. Compounds that mimic these signals may therefore be exploited as adjuvants in current vaccination strategies. Advances in molecular technology have permitted the design of ?subunit? vaccines directed at protein targets, providing immunotherapy with a degree of specificity that was not possible using traditional vaccines based on live attenuated viruses.
Preclinical Results: We have described the property of invariant NKT (iNKT) cells to assist priming of antigen specific T lymphocytes. The results of these experiments were derived from a concerted effort between immunologists, structural biologists and organic chemists.
Stimulation of iNKT cells in vivo significantly enhances immune responses to protein and peptide based vaccines, due to rapid iNKT dependent Dendritic Cell (DC) maturation. We have recently solved the crystal structure of CD1d molecules and measured the affinity of binding of soluble iNKT T cell receptor to CD1d molecules loaded with iNKT agonists. The results of these structural, kinetic and functional studies have led to the rational optimisation of a series of novel synthetic compounds capable of activating human and mouse iNKT cells, resulting in rapid DC maturation and T cell priming. Experiments carried out with human cells showed that the compound threitolceramide is capable of priming antigen specific T cells as efficiently as the iNKT cell agonist alpha-GalactosylCeramide.
Research Plan: We are requesting funding to carry out a phase I clinical trial in melanoma patients to test the ability of threitolceramide to assist priming and expansion of melanoma specific T cell responses. Since it has recently been shown that alpha-GalactosylCeramide pulsed DC can expand iNKT cells in patients, we intend to pulse DC with threitolceramide and with melanoma peptide epitopes derived from the Melan-A and NY-ESO-1 proteins and inject them into high risk melanoma patients. The results of this trial will provide a platform for the design of effective T cell and antibody therapy against infectious diseases and cancer.
Preclinical Results: We have described the property of invariant NKT (iNKT) cells to assist priming of antigen specific T lymphocytes. The results of these experiments were derived from a concerted effort between immunologists, structural biologists and organic chemists.
Stimulation of iNKT cells in vivo significantly enhances immune responses to protein and peptide based vaccines, due to rapid iNKT dependent Dendritic Cell (DC) maturation. We have recently solved the crystal structure of CD1d molecules and measured the affinity of binding of soluble iNKT T cell receptor to CD1d molecules loaded with iNKT agonists. The results of these structural, kinetic and functional studies have led to the rational optimisation of a series of novel synthetic compounds capable of activating human and mouse iNKT cells, resulting in rapid DC maturation and T cell priming. Experiments carried out with human cells showed that the compound threitolceramide is capable of priming antigen specific T cells as efficiently as the iNKT cell agonist alpha-GalactosylCeramide.
Research Plan: We are requesting funding to carry out a phase I clinical trial in melanoma patients to test the ability of threitolceramide to assist priming and expansion of melanoma specific T cell responses. Since it has recently been shown that alpha-GalactosylCeramide pulsed DC can expand iNKT cells in patients, we intend to pulse DC with threitolceramide and with melanoma peptide epitopes derived from the Melan-A and NY-ESO-1 proteins and inject them into high risk melanoma patients. The results of this trial will provide a platform for the design of effective T cell and antibody therapy against infectious diseases and cancer.
