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8 Biotech Companies Rethinking Immunotherapy for Brain Tumors


Growing evidence indicates that the field of cancer immunotherapy is coming of age. Here, a look at selective companies that are advancing immunotherapy approaches to brain tumors.


Amenable to Immunotherapy

Beyond recent observations suggesting a role for immunotherapy in treating brain tumors, several other factors make glioma an ideal indication for immunotherapy. First, glioma rarely metastasizes beyond the brain, resulting in a low overall tumor burden within the body. Second, while the blood-brain barrier is thought to restrict entry of immune cells from the peripheral blood into the brain of healthy individuals, glioma disrupts the blood brain barrier, allowing for the freer trafficking of T-cells. Finally, glioma tumor tissue, especially in patients who are newly diagnosed, is amenable to surgical resection therefore lowering tumor burden at time of vaccination [minimal residual disease]. Studying cancer immunotherapy in settings with bulky or metastatic disease might help explain some of the past failures, as the immune system may not be able to thwart such extensive disease. Accordingly, minimal disease settings are ideal for cancer immunotherapy.

Strategies for Immunotherapy in Glioma

In general, two categories of immunotherapeutic approaches for the treatment of glioma are currently being pursued: cell-free vaccines and cell-based vaccines.

Cell-free vaccines

Cell-free vaccines may contain heat-shock protein-peptide (HSP) complexes derived from the patient's tumor following surgery [autologous] or incorporate one or more defined tumor peptides plus an adjuvant [non-autologous]. The following companies are advancing cell-free vaccines:

  • Agenus, Inc. (AGEN): autologous HSPs that elicit both CD4+ and CD8+ T-cell response and also innate response
  • Celldex Therapeutics (CLDX): a single EGFRvIII peptide
  • Immatics Biotechnologies: 11 tumor associated, synthetic peptides
Cell-based vaccines

Cell-based vaccines often incorporate dendritic cells [DC] pulsed with defined tumor peptides, tumor cell lysate, brain tumor stem cell mRNA. Alternatively, some cell-based vaccines consist of adoptive lymphocyte infusion and/or irradiated tumor cells. The following companies are advancing cell-based vaccines:
  • ImmunoCellular Therapeutics (IMUC.OB): DCs pulsed with shared HLA-A1/A2 tumor peptides
  • Innocell Corp: adaptive transfer of cytokine-induced T-cells/NK cells
  • Northwest Biotherapeutics (NWBO.OB): DCs pulsed with tumor lysate
  • Oncovir, Inc.: a-type 1 polarized DCs pulsed with defined HLA-A2 peptides plus poly-ICLC adjuvant
  • TVAX Biomedical: whole cell vaccination plus adoptive transfer of lymphocytes
To date, commercializing cell-based vaccines has been challenging. For example, Dendreon's (DNDN) Provenge® [sipuleucel-T] for prostate cancer is a cell-based vaccine that fell short of Wall Street analyst expectations during the first full year of commercial launch. Provenge and other DC-based cancer vaccines require leukopherisis to acquire a patient's dendritic cells. This process adds to the overall cost of producing the vaccine and makes the logistics somewhat complicated. In contrast, cell-free vaccines can be derived from synthetic peptides or from the patient's tumor following standard surgical resection, making the treatment process more user friendly from both a physician and patient perspective.

Clinical Development of Immunotherapy for GBM

The current standard of care for GBM, based on a prospective, randomized controlled trial published in 2005, involves maximal surgical resection with adjuvant radiation therapy and temozolomide. Despite this therapeutic regimen, median overall survival is between 14.6 and 19.6 months for newly diagnosed patients and between 6 and 9 months for recurrent GBM.

While immunotherapy approaches for GBM would be expected to perform better in the newly diagnosed setting, some companies first established proof-of-concept for their product candidates in the relapsed setting. Due to the shorter expected survival, these Phase I/II studies may be faster and less expensive. If hints of efficacy are observed in the relapsed disease setting, the product candidates can then be explored in the newly diagnosed setting.

In view of differences among histologies, ages, trial designs, and the small number of patients with immunotherapy studies published to date in the recurrent GBM setting, comparing and contrasting the findings is difficult [see Table 2]. For example, in the largest single study [56 patients] from the Catholic University of Leuven, the median age was the lowest [45 years] due to the inclusion of children above the age of seven. In addition, some of the studies included patients that were not diagnosed with GBM, such as astrocytomas that can vary in grade.

In contrast to the results obtained with current standard of care, several of the studies with cancer vaccines for recurrent GBM have demonstrated a median overall survival greater than nine months. Some of these trials where immune responses have been measured, such as the Prophage G-200 [HSPPC-96] trial, have shown impressive immunological activity post vaccination. More impressive and certainly more relevant, these responses have also been measurable locally at the tumor site, which suggests such a response may be more meaningful from the perspective of effectively combating the disease.

Table 2. Recurrent GBM Vaccine Data

Several companies are also currently conducting immunotherapy trials in newly diagnosed GBM, with encouraging results presented to date, including Agenus [ NCT00905060], Celldex Therapeutics [ NCT01480479], Immatics [ NCT01222221], ImmunoCellular [ NCT01280552], Innocell Corporation [ NCT00807027], and Northwest Biotherapeutics [ NCT00045968].

An important future direction for the successful treatment of these very difficult tumors may involve the combination of immunotherapeutic agents with other synergistic treatments. Such approaches could simultaneously address the immunosuppressive, angiogenic, invasive, and hypoxic nature of GBM. In this regard, combination approaches with Avastin® [bevacizumab] and other potentially synergistic agents would make imminent sense to pursue.

Editor's note: For further information and a list of references, click here.
No positions in stocks mentioned.
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