Arnold Etame, MD, PhD
Moffitt Cancer Center
Neuro- Oncology Program
Immunotherapy is rapidly emerging as a very attractive and novel therapeutic approach for cancer, including for glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults.1
For patients with this malignancy, the current multimodal therapy of surgery, chemotherapy, and radiotherapy is often ineffective. Consequently, higher rates of tumor recurrence and progression are often the rule with GBM, and the prognosis is very dismal. Patients have a median survival of less than 15 months.2
Furthermore, by the fifth year of diagnosis, more than 90% of patients are likely to succumb to the disease.3
Novel and effective alternative therapeutic strategies are therefore essential.
With immunotherapeutic approaches, cancer- specific immune responses can occur through several non-mutually exclusive strategies. These include activation of the immune system with tumor antigens; neutralization of tumor antigens with antibodies; enhancement of immune-stimulatory signaling pathways that promote cytotoxic T-cell activity; or adoptive T-cell tumor–targeting mechanisms.
Most immune-based therapeutic strategies for GBM have focused on the concept of vaccines, with the overwhelming majority of applications based on dendritic cells (DCs). The DC vaccine strategy was pioneered through the development of sipuleucel-T for the treatment of castration- resistant prostate cancer (CRPC). In a landmark study,4
Kantoff and colleagues demonstrated a significant improvement in overall survival (OS) for patients with CRPC who were treated with sipuleucel-T, helping to establish the foundation and enthusiasm for applicability to other cancers.
Strong Rationale for DC Vaccines
DCs are particularly attractive in vaccine applications because of their exquisite, efficient ability to present foreign antigens as antigen-presenting cells (APCs) to the immune system, thereby generating an antigen-specific adaptive immune response. With this approach, expanded clones of autologous DCs pulsed with either GBM cell lysates or tumor-derived peptides are used for the vaccine (Figure
). It is anticipated that the DCs will recognize GBM cells bearing applicable antigens, thus leading to destruction of residual GBM tumor cells through adaptive immune-mediated mechanisms.
A major feature of this approach is its personalized cancer care focus, and the potential to target a broad range of tumor antigens. Potential limitations of this strategy include the requirement for surgical resection, as well as the labor-intensive and complex process of vaccine manufacturing. The safety, immunogenic potential, and effectiveness of DC vaccines pulsed with GBM tumor cell lysates or tumor-eluted peptides have been well established in preclinical5-10
as well as clinical studies.11-21
The preponderance of evidence suggests that the vaccine strategy is well tolerated, effective, and can improve overall survival in a tumor-specific, immune response–dependent fashion.
Figure. Typical Dendritic Cell (DC) Vaccine Scheme
Dendritic cells (DCs) obtained from differentiated monocytes in peripheral blood (red icon) are matured and then pulsed with tumor cell lysates, antigens, or peptides. The loaded cells are expanded and injected intradermally into patients, where the vaccine stimulates antitumor cytotoxic T lymphocytes (CTLs).
One of the largest clinical studies of DC vaccines in GBM was conducted by De Vleeschouwer and colleagues.17
They safely treated 56 patients with recurrent GBM with DCs pulsed with autologous tumor lysate as postsurgical adjuvant therapy. There was a marked tendency toward improvement in both progression-free survival (PFS) and OS within the vaccination group.