Therapeutic innovation in cancer treatment has always been in focus. In the past few years, cancer research has seen increased emphasis on personalized medicine and targeted therapies. Due to continuous advances and shift in treatment modalities, it is difficult for the treating physicians to keep up with the novel therapeutic approaches in cancer treatment. The International Cancer Alliance for Research and Education (ICARE), a multinational, nonprofit network of scientists and researchers, is committed to bringing emerging therapeutic options to patients and their treating doctors. ICARE has also focused on identifying, initiating and funding research projects targeting tumors of individual patients. The current discussion is about recent advances in brain cancer therapy. The most common and most aggressive type of brain cancer is called glioblastoma that can occur in the spinal cord or the brain. Also known as glioblastoma multiforme (GBM), it is very difficult to treat and a cure is often not possible. These tumors arise from the glial cells which surround nerve cells to provide support for nerve cells.
Available treatment options include surgery, radiation therapy and chemotherapy. Surgery to remove the maximum possible tumor tissue is the first step in treating most types of brain tumors. At many times, complete removal of tumors are not possible with surgery as tumors cannot be separated from surrounding tissues. Radiation therapy is usually recommended after surgery. Radiation therapy uses high beam radiation to kill tumor cells. Chemotherapy, which uses drug therapy to kill cancer cells, is often used during and after radiation therapy. One such chemotherapy drug is temozolamide (Temodar). Despite maximum surgical removal, high dose of radiation and chemotherapy, patients with newly diagnosed GBM have a short survival of less than 15 months. This is why more precise and efficacious therapies are desperately needed.
One such potential approach is to use immune based cancer chemotherapy that boosts the body’s natural defenses (immune system) to fight cancer. Such immuno-chemotherapy has the great advantage of being safer and less toxic than conventional chemotherapy drugs. The goal of immuno-chemotherapy is to identify the tumor specific substance known as antigen that induces an immune response in the body by producing antibodies (such as T-cells) which eventually targets tumor cells. Such targeted therapy works by targeting specific genes or proteins to help stop cancer from growing and spreading. Several research groups have demonstrated that human Cytomegalovirus (CMV) proteins are expressed in more than 90% of glioblastomas. CMV expression has not been detected in surrounding normal brain tissues which provide opportunity to target CMV proteins as tumor specific target. For a type of cancer such as GBM, it is likely a single drug will be insufficient to achieve therapeutic benefit in a majority of patients.
This article evaluates recent research and clinical trials related to CMV specific immune cancer therapy in combination with other chemotherapy for treatment of GBM. In a clinical trial conducted at Duke University, it has been demonstrated that patients who received vaccine targeting CMV antigen improved duration of survival of patients without progression of disease (progression free survival, PFS) and overall survival (OS). This improvement in PFS and OS was in comparison with previous historical data, known as historical controls. It has also been demonstrated that, dose intensified chemotherapy with temozolamide (TMZ) and immune growth factors for improving immunity (such as granulocyte macrophage colony-stimulating factor, GM-CSF to boost white blood cells production) when used in combination – can enhance immune responses to tumor-specific antigens in patients with glioblastoma. This is a first in human clinical trial (also known as phase I study) where patient safety was evaluated after vaccinating newly diagnosed GBM patients followed by dose intensified temozolamide (DI-TMZ) therapy. Patients’ immune response was also assessed, including PFS and OS in comparison with standard of care.
Materials and Methods
Adult patients with newly diagnosed grade IV GBM were the target population for this first in human trial. The trial was approved by the FDA and the Institutional Review Board at Duke University. Eligible patients completed a 6-week course of radiotherapy with concurrent daily dose of temozolomide at 75 mg per meter square of body surface area (mg/m2). After 4 weeks of this standard chemo-radiation therapy, imuno-chemotherapy was administered as a part of this trial.
Vaccination to target CMV sites of GBM
For the vaccine to work and activate the body’s defense system, Antigen Presenting Cells (APCs) are required. A Dendritic Cell (DC) is an APC which induces the generation of specific immune response from T-cells. A DC vaccine is made from the person in whom it is to be used. DCs are prepared by removal of immune cells from the patient’s blood (white blood cells) and exposure in the lab to cancer antigens which turn the immune cells into DCs and help them grow. The DCs are then injected back into the patient to generate an immune response to cancer cells in the body. Such DC vaccines are novel therapeutic strategy for cancer treatment. CMV specific DCs are admixed with immune growth factors (GM-CSF). For this trial DC vaccine 1 was administered on day 23 ± 1 of that 28-day cycle. Subsequent vaccinations were done at 2 weeks after first vaccination. Up to 3 vaccinations were targeted and further treatment was based on response from the patients.
Dose intensified temozolomide (DI-TMZ).
At 4 weeks following standard chemotherapy and radiation therapy, first treatment cycle of DI-TMZ was administered at dose 100 mg/m2 for 21 days of 28-day cycle. A repeat cycle of DI-TMZ was to be done after third vaccine
Patients were enrolled over the course of 2 years and a lock date 4.25 years after the last patient enrolled was applied for survival analysis. Study was targeted to recruit at least 6 evaluable patients.
Treatment comparison was made with group of patients who have undergone conventional chemo-radiation therapy in past. This group is termed as a historical control. Historical controls consisted of 23 patients’ data (almost double than treatment therapy under investigation) which was randomly selected from the large database of patients who have undergone surgical removal of tumor and were treated at Duke University Medical Center over the course of 2 years. Historical controls were treated similarly to study patients with initial gross total surgical removal and standard 6-week radiation therapy and temozolomide therapy. If no progressive disease occurred at this point, historical controls proceeded to receive monthly standard TMZ cycles (150–200 mg/m2 per day for 5 days) and did not receive any other therapies until progression.
Various assessment such as immunogenic responses and radiographic changes such as MRI were also carried out prior to vaccine 1 (baseline), after 3 vaccines and at various times thereafter.
A total of 14 patients were initially enrolled in the study. The study therapy was considered completed when DI-TMZ cycle 1 and DC vaccines 1 to 3 were administered without additionally prescribed therapies. Three patients were withdrawn/discontinued from the study as they were not meeting trial specified criteria and analysis is based on the remaining 11 patients’ data. All 11 patients received at least 7 vaccines of pp65-DCs and were eligible to receive a maximum of 10 total vaccines if they had
not progressed. Patients in this study administered at least 3 vaccines of pp65-DCs with concomitant DI-TMZ showed significantly increased PFS and OS compared with historical controls. Immunogenic response were assessed prior to vaccination (baseline) and after three vaccines. The 4 long-term survivors in this study received 10 vaccines, and each demonstrated an expansion in vaccine responses following DC vaccines 1–3 when DI-TMZ was withheld. Long-term survivors, with OS > 40 months
showed a much more significant vaccine responses after 3 vaccines from baseline (prior to vaccine 1) compared with those with OS < 40 months.
This study validates prior studies targeting CMV antigen in newly diagnosed GBM and demonstrates that CMV vaccines can increase immunity despite immune suppressing effect due to DI-TMZ, and leading to unexpectedly prolonged survival (both PFS and OS) compared to historical controls. This study suggests that DI-TMZ is more efficacious if used in with antigen-specific vaccination for GBM. Timing of vaccination in relation to DI-TMZ or other immune-suppressing chemotherapy drug is an important consideration in generating robust immune responses. As GBM patients become part of the research movement and have a direct impact on treatment, ICARE makes treatment options available where results strengthen prior findings from other trials targeting CMV and provide evidence for the association between targeted immune therapy in GBM and long-term survival.