Researchers believe that being able to generate an effective immune response against intractable brain cancers could be the key to prolonging the current dismal survival statistics that patients face following diagnosis of glioblastoma multiforme (GBM). Immunotherapies, using cancer vaccines and gene therapy approaches, have in early testing yielded encouraging results leading to the hope that they will eventually become integrated into the current standard of care for this serious disease.

PERSONALIZED MEDICINE

A personalized medicine approach to GBM is being employed by the first European Union-funded initiative aimed at clinically developing biomarker-guided actively personalized vaccines (APVACs) to treat patients. Known as the Glioma Actively Personalized VAccine Consortium (GAPVAC), it will be led by cancer vaccine specialist Immatics Biotechnologies GmbH, of Tuebingen, Germany, and Biontech AG, of Mainz, Germany.

The consortium includes 14 organizations in Europe and the U.S. and is supported by a €6 million (US$7.5 million) grant from the European Union Framework 7 program.

In October, GAPVAC received the green light to begin a phase I/II study, GAPVAC-101, which it is claimed involves for the first time the concept of treating glioblastoma patients with drugs designed and manufactured for each patient individually according to specific characteristics of their tumors and immune systems.

Screening of first patients for the trial has started and manufacturing of the personalized vaccines will be performed by the GMP unit of the University of Tuebingen in close cooperation with the GMP and core services platform of the German Cancer consortium.

The trial will recruit up to 30 newly diagnosed glioblastoma patients with the endpoint aiming to show that APVACs are well tolerated and induce a strong and specific response against cancer, as well as demonstrating the feasibility of the treatment approach. Each patient will be immunized with two vaccines specifically prepared for them. The first will be a tailored selection of 70 peptides based on the target profile of the individual cancer tissue and the ability of the individual's immune system to induce a response to the selected targets. The second vaccine will be based on full next-generation sequencing (NGS)-based genetic analysis of the patient and will comprise peptides newly manufactured by consortium partner University of Tuebingen. The latter vaccine will largely target mutations occurring in cancer tissue but not in healthy tissue. Both actively personalized vaccines will be designed according to biomarker-guided procedures performed at Immatics and Biontech and will be administered in addition to standard chemotherapy after surgery and initial radiochemotherapy are completed. The trial is being accompanied by an extensive biomarker program involving the Association of Cancer Immunotherapy, a nonprofit organization dedicated to the advancement of cancer vaccines.

HEAT-SHOCK PROTEIN

Individualizing cancer vaccines is an approach also being taken by Agenus Inc., of Lexington, Mass., which uses heat-shock protein (HSP) gp96, purified from the patients' own tumor tissues.

In July, the company reported promising final results from a single-arm, multi-institutional, open-label, phase II study showing that patients with newly diagnosed GBM who received its HSP Prophage autologous cancer vaccine added to the standard of care treatment did live longer. The study found that vaccine-treated patients in the study had a median progression-free survival (PFS) of almost 18 months, about two to three times longer than patients treated with radiation and the alkylating agent temozolomide alone. Twenty-two percent of patients were alive and without progression at 24 months and will continued to be followed for survival outcomes. (See BioWorld Today, July 2, 2014.)

The company noted that the response to Prophage seems to be more pronounced in those patients with less expression of the checkpoint ligand PDL-1 on the white blood cells, suggesting that combinations of Prophage with checkpoint modulators like PD-1 antagonists might make Prophage even more effective in a greater percentage of patients with GBM.

Tvax Biomedical Inc., of Lenexa, Kan., said it raised $2 million in the first closing of a private round of financing. The company intends to use the proceeds to continue the clinical development of its immunotherapy platform, a personalized combination of cancer cell vaccination and T-cell treatment. The company said it plans to raise a total of $10 million as part of the round. TVI-Brain-1 is the company's lead candidate, which has received orphan product designation for the treatment of primary central nervous system malignancies, including brain cancer, and is being advanced as a treatment for patients with recurrent glioblastoma. (See BioWorld Today, Jan. 8, 2013.)

Late last year there was a disappointment for Immunocellular Therapeutics Ltd.'s dendritic cell-based vaccine ICT-107 in GBM. In an exploratory phase II trial, the compound hit the secondary PFS endpoint in newly diagnosed GBM patients, but missed the primary overall survival endpoint. (See BioWorld Today, Dec. 13, 2013.)

However, in September the firm disclosed plans to advance ICT-107 to a registrational phase III program anticipated to start in mid-2015 in patients with newly diagnosed glioblastoma. That followed "supportive feedback from both the FDA and European national regulatory authorities on the phase II results," noted Andrew Gengos, Immunocellular's CEO.

The company said it will present the next set of updated efficacy data at the Society for Neuro-Oncology (SNO) meeting in Miami next week.

GENE THERAPY

Another company eagerly anticipating presenting its findings at the meeting is San Diego-based Tocagen Inc. CEO Harry Gruber told BioWorld Insight he is hoping that the new data will be seen as "a significant breakthrough in brain cancer treatment."

The company is focused on a combination therapy strategy designed to deliver a virus, Toca511, which is employed with Toca FC, an extended-release tablet containing the prodrug 5-FC (flucytosine).

The gene therapy agent, Toca511, a retroviral replicating vector, contains an extra cytosine deaminase (CD) gene, which is not present in human cells, that is administered by several routes – during the time of surgery to remove the tumor, by intravenous delivery, or through a minimally invasive neuro-navigation procedure to inject the virus directly into the tumor.

The immune defenses of a normal cell will typically eliminate the virus, but cancer cells have defective immune defenses, which means once the vector is delivered to the tumor it can replicate without being detected. The virus is allowed to spread through the tumor cells over the course of one or two months depending on the clinical setting, Gruber explained. The tablet is taken by the patient in cycles of one week out of every month.

The CD enzyme catalyzes the conversion of the antifungal drug 5-FC to the powerful and highly toxic anticancer agent 5-FU (5-fluorouracil) inside the cancer cells, which selectively destroys them.

Preclinical data have shown that Toca 511 can hide in the cancer environment and spread from cancer cell to cancer cell, thereby allowing targeted delivery of a potent cancer drug selectively to the cancer tissue while leaving healthy tissue unharmed.

The treatment has already shown promising results in animals. In rodents the company found that three cycles of activation of 5-FU were sufficient to prolong survival compared to the control (nontreated and Toca 511-only-treated) animals.

Also, in early trials looking at escalating doses they have been able to observe important tumor shrinkage and survival, Gruber explained.

The company now believes that with the safety and efficacy data that to date it is poised to begin a program for registration trials for the combination treatment.