Low-grade gliomas (LGG), the most common of which are pilocytic astrocytomas, diffuse
astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas are a diverse family of
central nervous system (CNS) neoplasms that occur in children and adults. Based on data from
the American Cancer Society and Central Brain Tumor Registry of the United States (CBRTUS),
approximately 1800 LGG were diagnosed in 2006, thus representing approximately 10% of newly
diagnosed primary brain tumors in the United States. Pilocytic astrocytomas (WHO grade I) are
the most common brain tumor in children 5 to 19 years of age3. Diffuse astrocytomas,
oligodendrogliomas, and oligoastrocytomas are all considered WHO grade II low grade gliomas
(LGG) and are more common in adults. Pilocytic astrocytomas are generally well circumscribed
histologically and radiographically and amenable to cure with gross total resection. In
contrast, the diffuse astrocytomas, oligodendrogliomas, and oligoastrocytomas are more
infiltrative and less amenable to complete resection. From a molecular genetics standpoint,
the most common alterations in LGG are IDH1 mutations6 and mutations in the tumor suppressor
gene TP53, located on chromosome 17, the gene product of which is a multifunctional protein
involved in the regulation of cell growth, cell death (apoptosis), and transcription.
Additionally, several molecular factors are of favorable prognostic significance,
particularly the presence of 1p/19q co-deletion and IDH1 mutations.
WHO grade II LGGs are at extremely high risk to undergo malignant transformation into more
aggressive and lethal WHO grade III or IV high-grade glioma (HGG). Even with a combination of
available therapeutic modalities (i.e., surgery, radiation therapy [RT], chemotherapy), the
invasive growth and resistance to therapy exhibited by these tumors results in recurrence and
death in most patients. Although postoperative RT in LGG significantly improves 5-year
progression-free survival (PFS), it does not prolong overall survival (OS) compared with
delayed RT given at the time of progression. Early results from a randomized trial of
radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy for
supratentorial adult LGG (RTOG 9802) demonstrated improved PFS in patients receiving PCV plus
RT compared RT alone. Nonetheless, PCV is considerably toxic and currently not widely used
for management of glioma patients. Although chemotherapy with temozolomide (TMZ) is currently
being investigated in LGG patients, it is unknown whether it confers improves OS in these
patients. Further, our recent study has indicated that 6 of 10 LGG cases treated with TMZ
progressed to HGG with markedly increased exome mutations and, more worrisome, driver
mutations in the RB and AKT-mTOR pathways, with predominant C>T/G>A transitions at CpC and
CpT dinucleotides, strongly suggesting a signature of TMZ-induced mutagenesis; this study
also showed that in 43% of cases, at least half of the mutations in the initial tumor were
undetected at recurrence. These data suggests the possibility that treatment of LGG patients
with TMZ may enhance oncogenic mutations and genetic elusiveness of LGG, therefore calling
for development of safer and effective therapeutic modalities such as vaccines.
Taken together, LGG are considered a premalignant condition for HGG, such that novel
interventions to prevent malignant transformation need to be evaluated in patients with LGG.
Immunotherapeutic modalities, such as vaccines, may offer a safe and effective option for
these patients due to the slower growth rate of LGG (in contrast with HGG), which should
allow sufficient time for multiple immunizations and hence high levels of anti-glioma
immunity. Because patients with LGGs are generally not as immuno-compromised as patients with
HGG, they may also exhibit greater immunological response to and benefit from the vaccines.
Further, the generally mild toxicity of vaccines may improve quality of life compared with
chemotherapy or RT.
Inclusion Criteria:
- Pathological criteria - Patients must have newly diagnosed or recurrent WHO grade II
glioma (defined as an astrocytoma, oligodendroglioma, or oligoastrocytoma) that is to
be histologically confirmed by clinically indicated resection. If patients have
already undergone biopsy and have pathological diagnosis of WHO grade II glioma,
pathology must be reviewed and confirmed at University of California, San Francisco
(UCSF).
- Before enrollment, patients must show supratentorial, non-enhancing T2-FLAIR lesions
that need to be surgically resected and are likely WHO grade II glioma. Surgical
resection of at least 500 mg tumor tissue to ensure adequate evaluation of the study
endpoints.
- Prior radiation therapy (RT) after the initial diagnosis will be allowed. Patients
with prior RT must be at least 6 months from the completion of RT (or radiosurgery)
- Prior chemotherapy or molecularly targeted therapy will be allowed. Patients with
prior chemotherapy must be at least 6 months from the last dose of chemotherapy or
molecularly targeted therapy
- Patients must be ≥ 18 years old
- Patients must have a Karnofsky performance status ≥ 70%
- Patients must be off corticosteroid for at least for 2 weeks before the first
neoadjuvant vaccine and for at least 2 weeks prior to the first adjuvant vaccine
- Adequate organ function within 14 days of study registration including:
- Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count
(ANC) ≥1.0 x 10^9/L; absolute lymphocyte count (ALC) ≥0.5 x 10^9/L; platelets
≥100 x 10^9/L; hemoglobin ≥8 g/dL;
- Hepatic: - Total bilirubin ≤1.5 x upper limit of normal (ULN) and serum
glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase (ALT)) ≤ 2.5 x
upper limit of normal (ULN), and
- Renal: Normal serum creatinine or creatinine clearance ≥60 ml/min/1.73 m^2
- Must be free of systemic infection. Subjects with active infections (whether or not
they require antibiotic therapy) may be eligible after complete resolution of the
infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days
before beginning treatment.
- Sexually active females of child bearing potential must agree to use adequate
contraception (diaphragm, birth control pills, injections, intrauterine device (IUD),
surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration
of the vaccination period. Sexually active males must agree to use barrier
contraceptive for the duration of the vaccination period.
Exclusion Criteria:
- History of immune system abnormalities such as hyperimmunity (e.g., autoimmune
diseases) and hypoimmunity (e.g., myelodysplastic disorders, marrow failures, AIDS,
transplant immunosuppression)
- History or clinical suspicion of neurofibromatosis
- Any isolated laboratory abnormality suggestive of a serious autoimmune disease (e.g.
hypothyroidism)
- Any conditions that could potentially alter immune function (AIDS, multiple sclerosis,
uncontrolled diabetes, renal failure)
- Receiving ongoing treatment with immunosuppressive drugs
- Currently receiving any investigational agents or registration on another therapy
based trial
- Pregnant or lactating
