Tag: Prof. Cornelis Melief

Company News: ISA Pharmaceuticals Announces Start of First Phase I/II Clinical Trial of its SLP®-AMPLIVANT® Conjugates

– Leiden University Medical Center to study novel immunotherapeutic in HPV-positive head & neck cancer patients

ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed immunotherapeutics against cancer and persistent viral infections, has announced the start of an investigator-initiated Phase I/II clinical trial of a novel immunotherapeutic based on ISA Pharmaceuticals´ platform technology. The trial will be conducted by the Department of Clinical Oncology at Leiden University Medical Center in The Netherlands. The study will investigate the biological activity and safety of the compound in head and neck cancer patients who tested positive for human papilloma virus type 16 (HPV16). HPV infections, in particular HPV16, are one of the major causes of this type of cancer. The immunotherapeutic is a conjugate of two HPV16 E6 Synthetic Long Peptides (SLP®s) covalently linked to AMPLIVANT®, a synthetic Toll-like receptor (TLR) 1/2 ligand. The investigators have assigned the acronym HESPECTA to the conjugate (HPV E-Six Peptide Conjugated To AMPLIVANT®).

In the single-center, open-label dose escalation study, 24 HPV16-positive head and neck cancer patients will be grouped into four dose escalation groups. In each group, every patient will receive three intradermal doses of the immunotherapeutic. The primary endpoint is to assess its ability to induce HPV16 E6-specific T-cell immunity. The secondary endpoint is to evaluate the safety of the intervention.

The human papillomavirus is associated with several types of cancer, of which HPV16 is by far the most common high-risk HPV type detected. It encodes the two tumor-specific oncoproteins E6 and E7 which are known to also induce and maintain the malignant state of the transformed cells. This SLP®-AMPLIVANT® conjugate aims to induce a strong, lasting immune response against the tumor.

AMPLIVANT®, developed by ISA Pharmaceuticals, is based on a Toll-like receptor ligand (TLR1/2 ligand), one of the most powerful natural stimulants of the immune system. SLP®-AMPLIVANT® conjugates have demonstrated to be 100- to 1000-fold more potent in inducing an immune response compared to unconjugated SLP®s in preclinical and mouse tumor models.

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 in Nature Supports ISA Pharmaceuticals´ Synthetic Long Peptide Immunotherapeutic Approach to Treat Cancer

Synthetic Long Peptide (SLP®) immunotherapy achieves targeted tumor eradication comparable to checkpoint-blocking immunotherapy

New findings on antigens relevant for checkpoint blocking pave the way for personalized cancer vaccines

ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed immunotherapeutics against cancer and persistent viral infections, today announced that a recent scientific paper in Nature supports the company´s therapeutic approach to using synthetic long peptides in cancer therapy. It could be shown that personalized SLP® immunotherapy is as capable of inducing efficient tumor eradication as are T cell checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies. The research was conducted by a consortium led by Prof. Robert D. Schreiber from Washington University St. Louis. Prof. Cornelis Melief, Willem-Jan Krebber, and Gwenn E. Mulder from ISA Pharmaceuticals also participated in the project.

It is well known that checkpoint immune regulators on the surface of T cells act as deactivators. While they are useful in preventing T cells from attacking healthy tissues, in cancer they prevent the T cells from destroying tumor cells. Checkpoint blockers, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, that target these proteins are very effective in restoring the T cell’s ability to eradicate tumor cells. In the Nature publication, Matthew M. Gubin and co-workers – among them three ISA researchers – report about their identification of the antigens recognized by these tumor-infiltrating T cells once their activity has been restored. The researchers used a mouse model of carcinogen-induced cancer, which – like human lung cancer from smokers – bears many mutations (e.g. caused by tar).

The researchers demonstrated that the T cells previously blocked by checkpoint immune regulators were directed against two mutant antigens on the cancer cell surface. These T cells had already infiltrated the tumor prior to checkpoint blocking, but were subsequently deactivated by the tumor microenvironment. Moreover, the team showed that an immunotherapy consisting of two synthetic long peptides, each incorporating one of the mutant amino acid sequence admixed with the adjuvant poly I:C, was able to eradicate the tumor as effectively as checkpoint immunotherapy.

Personalized synthetic long peptides against tumor-unique mutant sequences are a promising treatment approach for cancers with many mutations, such as smoking-induced lung cancer and UV-induced skin cancer. Compared to checkpoint blocking, personalized immunotherapy is likely to achieve anti-tumor effects with less toxicity because they do not activate T cells that are able to attack healthy tissue.

Company News: New Clinical Data Demonstrate Strong Synergy between Cancer Vaccine ISA101 and Chemotherapy

–      Data presented at the AACR Annual Meeting 2014

–      Potential new treatment being developed for patients with late-stage cervical cancer

ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, has announced new clinical data on its lead product candidate ISA101. ISA101 is a therapeutic cancer vaccine for the treatment of high-risk, HPV16-induced diseases, such as cervical cancer. The data were presented by principal investigator Prof. Sjoerd van der Burg, Ph.D., at this year’s American Association for Cancer Research (AACR) Annual Meeting in San Diego.

The data demonstrate strong synergy between ISA101 and chemotherapy, offering potential new treatment options for cervical cancer patients scheduled to receive standard chemotherapy with carboplatin / paclitaxel.

Prof. van der Burg and his group evaluated the immunological and clinical responses of patients with advanced cervical carcinoma in a Phase I combination trial. In this pilot trial, patients received ISA101 in combination with standard chemotherapy cycles (carboplatin / paclitaxel). Almost all patients showed a strong immune response to the ISA101 vaccine. Comprehensive immune monitoring confirmed the beneficial effect of myeloid suppressor cell depletion associated with a robust induction of HPV16-specific T-cell responses that were sustained throughout several cycles of chemotherapy.

The observation that depletion of myeloid suppressor cells by a carboplatin/paclitaxel chemotherapy regimen enhances the immune response to ISA101 is in line with prior observations that tumors promote immune tolerance starting early in the disease and that chemotherapy can restore immune competence in cancer patients.

Based on these results ISA has initiated a phase I/II study (CervISA) in October last year testing ISA101 in combination with carboplatin, paclitaxel and pegylated interferon alpha in women with advanced or recurrent cervical cancer.

The presentation titled “Synergistic effects of properly timed HPV16 SLP vaccination during standard carboplatin-paclitaxel chemotherapy in animals and patients with metastatic cervical carcinoma“ was given at the Minisymposium MS.IM02.01 “Immune-based Therapies: Responses, Biomarkers, and Mechanisms” on Monday, April 07, 2014, at 3:20 PM in Room 6CF at the San Diego Convention Center.

The abstract # 2938 is available at the AACR website www.aacr.org.

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