Tag: peer-reviewed paper
Company News: ISA Pharmaceuticals – New Study Explains Synergy between Cancer Vaccine ISA101 and Chemotherapy
– Tumor necrosis factor alpha (TNFα) produced by T cells following vaccination sensitizes tumor cells for eradication by certain chemotherapeutics
– Data published in Clinical Cancer Research support ongoing clinical development of ISA101
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed immunotherapeutics against cancer and persistent viral infections, has announced new findings on the synergy between its synthetic long peptide (SLP®) cancer vaccine and chemotherapeutics. Data published in Clinical Cancer Research* demonstrate that combined chemo-immunotherapy leads to superior T cell-mediated tumor eradication in the absence of T cell immunosuppression.
In a preclinical model of cancer induced by human papillomavirus type 16 (HPV16), ISA’s lead SLP® candidate ISA101 was combined with seven clinically relevant chemotherapeutics to treat established tumors. The researchers tested either ISA101 or chemotherapeutics alone as well as combinations of both. Topotecan, gemcitabine, carboplatin and cisplatin showed synergies with ISA101. The most effective combination was cisplatin plus ISA101, resulting in tumor regression and the durable survival of 75% of the mice, and a lasting immune response. Most importantly, synergy occurred to the same extent at only 40% of the maximum tolerated dose (MTD) of cisplatin, allowing for a reduction of chemotherapy-associated side effects as seen at MTD. There was no synergy between ISA101 and oxaliplatin, doxorubicin or paclitaxel.
While synergy was not related to overt changes in systemic T cell immunity or increased sensitivity of cisplatin-treated TC-1 tumor cells towards CTL-mediated killing, there was a strongly enhanced leukocyte infiltration of the tumor. Vaccine-specific polyfunctional CD8 T cells were a major component of this infiltration. The cisplatin allowed these cells to migrate earlier into the tumor beds, enabling them to eliminate tumor cells at an earlier stage of disease. Once inside the tumor, the T cells further enhanced tumor cell death by producing pro-inflammatory cytokines such as IFNγ and TNFα. In particular, TNFα produced by intratumoral T cells sensitized the tumor cells for cisplatin, allowing for synergistic cell death.
Another study presented at AACR in 2014, showed that cis-/carboplatin/paclitaxel depletes myeloid derived suppressor cells in patients, and thereby strongly increases an ISA101-mediated immune response.
This finding supports the ongoing clinical development program in which ISA101 is tested in a Phase I/II study (CervISA) in combination with cisplatin/carboplatin and paclitaxel in women with advanced or recurrent cervical cancer.
* van der Sluis TC et al.: Vaccine-induced Tumor Necrosis Factor producing T-cells synergize with cisplatin to promote tumor cell death. Clin Cancer Res. 2014 Dec. 12 pii: clincanres.2142.2014; Epub 2014 Dec. 12,; doi: 10.1158/1078-0432.CCR-14-2142
Company News: Publication Demonstrates Superior Activity of ISA Pharmaceuticals´ SLP® Vaccines Compared to Whole Protein Vaccines
– Study published in European Journal of Immunology elucidates different, improved antigen presentation and T cell-inducing power of SLP® vaccines
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced the publication of a peer-reviewed paper in the European Journal of Immunology.[1] The article describes a previously unknown mechanism that explains the excellent efficacy of ISA’s Synthetic Long Peptide (SLP®) vaccines. The authors demonstrate that compared to whole protein antigens, SLP®s are processed much more rapidly and efficiently by dendritic cells (DCs), resulting in an increased antigen presentation to CD4+ and CD8+ T cells, and enhanced CD8+ T cell activation. The improved presentation relates to a distinct intracellular localization of SLP®s after uptake by DCs.
Cancer immune therapy requires the induction of potent CD4+ and CD8+ T cell responses to the malignant cells. This is accomplished by DCs, the major antigen-presenting cells of the immune system. So far it has been challenging to induce a sufficiently potent reaction by vaccinating with whole protein antigens. In a number of preclinical and clinical studies, ISA Pharmaceuticals has already observed improved efficacy of its SLP® vaccines as compared to whole protein vaccines.
To study the underlying mechanism, researchers used both mouse and human DCs. They found that after incubation with SLP® vaccines and subsequent uptake by the DCs, the SLP®s are located in the cell, but are largely outside the cells’ endosomes. In contrast, protein antigens are processed inside endosomes, resulting in a much slower and different processing route. In the study, SLP®s were processed far more efficiently and distinctly into both MHC class I and II antigen presentation pathways than whole protein antigens. This lead to a strong activation of both CD4+ and CD8+ T cells, resulting in potent and efficient immune responses to the antigen.
In previously published clinical studies, ISA had already demonstrated the superiority of SLP® vaccines over short peptide vaccines. Short peptide vaccines, which fit precisely into MHC class I molecules, often do not result in a sufficiently long antigen presentation, and also carry the risk of inducing a mix of favorable pro-immunogenic and detrimental tolerogenic signals. Moreover, short peptide vaccines do not instate efficient immunologic memory. ISA also demonstrated that these differences are caused by the highly selective uptake, processing and presentation of SLP®s by professional antigen-presenting cells, and by the presence of both CD4 and CD8 epitopes in the long peptides.
[1] Rosalia et al.; “Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T-cell activation”, DOI: 10.1002/eji.201343324
http://onlinelibrary.wiley.com/doi/10.1002/eji.201343324/abstract;jsessionid=F0FBA5A73F264503207C22EDF313FAB0.d04t03.