Tag: Clinical Cancer Research

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: Three Peer-Reviewed Papers by ISA Pharmaceuticals Introduce Strategies to Improve Immunotherapy Against Cancer

–  Local Delivery of Checkpoint Control Antibodies Greatly Improve Efficacy and Safety

–  Promising Potential for Combinatorial Strategies

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 three peer-reviewed papers that demonstrate the benefit of local delivery of a checkpoint control antibody targeting CTLA-4 (cytotoxic T lymphocyte antigen-4) for the successful eradication of cancer and the reduction of side effects. The papers include a review that underlines the importance of strategies for combinatorial treatments to improve further the immunotherapy of cancer. ISA Pharmaceuticals is developing cancer immunotherapies along those lines, in particular its Synthetic Long Peptide (SLP®) vaccine ISA101 for the treatment of HPV-induced diseases, such as cervical cancer and head and neck cancer, and ISA203 for the treatment of various tumors including lung cancer, head and neck cancer, breast cancer and melanoma.

In a paper just published in Clinical Cancer Research [1], a team of scientists from Leiden University Medical Center (LUMC) and ISA Pharmaceuticals report that in preclinical mouse models of cancer, the injection of a CTLA-4 blocking antibody in a slow-release formulation close to the tumor is very effective in activating a systemic anti-tumor (CD8+) T cell response. CTLA-4 is a crucial immune checkpoint protein that down-regulates the body’s immune response. The low-dose local treatment (50μg subcutaneously in a slow-release vehicle) eradicates tumors, including distant tumors, as effectively as a high-dose systemic treatment (2×200μg intraperitoneally). The method also leads to a 1000-fold decrease of antibody levels in the serum, thereby reducing adverse events and the risk of autoimmunity.

These findings are supported by an increasing number of studies demonstrating that local targets, mainly present in the microenvironment of tumors and draining lymph nodes, are key players in tumor progression. As published in a second paper by researchers from LUMC and ISA, a review in the International Journal of Cancer [2], local immunotherapies have clear advantages over systemic treatments, both in their ability to shift tumor-promoting mechanisms towards effective tumor-eradicating immunity and in terms of reducing the risks of systemic administration.

In the third publication in Seminars in Immunology [3], current cancer immunotherapy approaches are reviewed, concluding that most standalone immunotherapeutic strategies either fail to affect progressive diseases and survival significantly – or only do so in a minority of patients. The authors support combinations of synthetic vaccines that stimulate tumor-specific T cell responses and adjuvants, immune-modulating antibodies, cytokines, or chemotherapy.

 


[1] Fransen MF et al. (2103), Clin Cancer Res, Published Online First June 20, 2013; doi: 10.1158/1078-0432.CCR-12-0781

[2] Fransen MF et al. (2013), Int. J. Cancer, 132: 1971–1976; doi: 10.1002/ijc.27755

[3] Arens R et al., (2013), Sem Immunol, Published Online First May 21, 2013;
doi: 10.1016/j.bbr.2011.03.031