DC Migration Study for Newly-Diagnosed GBM

A maximum of 100 patients with resected, newly-diagnosed World Health Organization (WHO)
Grade IV GBM will be enrolled in this study with the expectation that approximately 79
patients will be randomized to subsequent treatment after completion of radiation treatment
with concurrent temozolomide. Effective March 2017, randomization to Group III has been
terminated. All consented patients will undergo a leukapheresis after resection for harvest
of Peripheral Blood Lymphocytes (PBLs) for generation of DCs. Patients will then receive
Radiation Therapy (RT) and concurrent TMZ at a standard targeted dose of 75 mg/m^2/d.
Patients should start RT within approximately 6 weeks of surgery. Patients who experience
progressive disease during radiation, are dependent on steroid supplements above physiologic
levels at time of first vaccination, are unable to tolerate TMZ, or whose DCs or PBLs fail to
meet release criteria will be withdrawn from the study and replaced and will not undergo
repeat leukapheresis. For patients whose initial leukapheresis yields less than 3 vaccines,
repeat leukapheresis may be obtained a minimum of 2 weeks from the previous leukapheresis
(and may be repeated as needed) if pre-pheresis blood work is within the Apheresis Center's
parameters and as long as this does not cause a significant delay in treatment for the
patient.

After RT and concurrent TMZ, patients will then be randomized and begin the initial cycle of
TMZ at a standard targeted dose of 150-200mg/m^2/d for 5 days at the discretion of the
treating oncologist 4 (± 2) weeks after completing RT. The study cycle of TMZ comprises a
targeted dose of 150-200mg/m^2/d for 5 days every 5 (± 1) weeks. All patients will receive up
to a total of 10 DC vaccines given bilaterally at the groin site unless progression occurs.
DC vaccines will be given intradermally (i.d.) and divided equally to both inguinal regions.
DC vaccines #1-3 will be given every two weeks, thus delaying the initiation of TMZ cycle 2.
Patients will then be vaccinated in conjunction with subsequent TMZ cycles every 5 (± 1)
weeks for a total of 6 to 12 cycles after RT at the discretion of the treating oncologist.
DCs will be given on day 21 ± 2 days of each TMZ cycle. DC vaccinations will continue during
TMZ cycles up to a total of 10 unless progression occurs.

Before the first DC vaccination, all patients will receive immunization with 0.5 mL of Td
intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen.
Those assigned to Group III will receive basiliximab 20 mg infusions 1 week before the 1st
and 1 week before the 2nd vaccine. At the time of the fourth DC vaccine, patients will
receive pre-conditioning per the assigned group (Group I-unpulsed DCs i.d.; Group II- Td
i.d.; Group III-Td i.d.). A single dose of Td toxoid (1 flocculation unit, in 0.3 milliliters
(mLs) of saline for a total volume of 0.4 mLs) or 0.4 mLs of 1 x 10^6 autologous unpulsed DCs
in saline will be administered to a single side of the groin, and 0.4 mLs of saline
administered to the contralateral side 12-24 hours prior to the fourth DC vaccine, which is
always given bilaterally at the groin site. Patients in Groups I and II will then receive
111In-labeled DCs to compare the effects of different skin preparations on DC migration
followed by Single-Photon Emission Computed Tomography and Computed Tomography (SPECT/CT)
imaging immediately and at 1 and 2 days after injection. Group III will not undergo migration
studies. Groups I and II will be double blinded. Group III will not be blinded.

All patients will undergo leukapheresis again for immunologic monitoring with specific
assessment of baseline antigen-specific cellular and humoral immune responses and further DC
generations 4 (± 2) weeks after vaccine #3. Patients will be imaged bimonthly without
receiving any other prescribed anti-tumor therapy. Patients will undergo an additional
leukapheresis for generation of DCs if needed to continue vaccinations.

As part of standard care for these patients, upon tumor progression, participants may undergo
stereotactic biopsy or resection. As this is not a research procedure consent will be
obtained separately. However, if tissue is obtained, it will be used to confirm tumor
progression histologically and to assess immunologic cell infiltration and pp65 antigen
escape at the tumor site.

Inclusion Criteria:

- Age ≥18 years of age

- WHO Grade IV Glioma with definitive resection prior to enrollment, with residual
radiographic contrast enhancing disease on the post-operative CT or Magnetic Resonance
Imaging (MRI) of <1 cm in maximal diameter in any axial plane

- MRI post radiation therapy (RT) does not show progressive disease at time of
randomization

- Karnofsky Performance Status of > 80%.

- Hemoglobin ≥ 9.0 g/dl, Absolute Neutrophil Count ≥ 1,500 cells/µl, platelets ≥ 125,000
cells/µl

- Serum creatinine ≤ 1.5 mg/dl, Serum Glutamic Oxaloacetic Transaminase & bilirubin ≤
1.5 times upper limit of normal

- Signed informed consent approved by the Institutional Review Board

- Female patients must not be pregnant or breast-feeding. Female patients of
childbearing potential (defined as < 2 years after last menstruation or not surgically
sterile) must use a highly effective contraceptive method (allowed methods of birth
control, [i.e. with a failure rate of < 1% per year] are implants, injectables,
combined oral contraceptives, intra-uterine device [IUDs; only hormonal], sexual
abstinence or vasectomized partner) during the trial & for a period of > 6 months
following the last administration of trial drug(s). Female patients with an intact
uterus (unless amenorrhea for the last 24 months) must have negative serum pregnancy
test within 48 hours prior to first study procedure (leukapheresis).

- Fertile male patients must agree to use a highly effective contraceptive method
(allowed methods of birth control [i.e. with a failure rate of < 1% per year] include
a female partner using implants, injectables, combined oral contraceptives, IUDs [only
hormonal], sexual abstinence or prior vasectomy) during the trial & for a period of >
6 months following the last administration of trial drugs

Exclusion Criteria:

- Pregnant or breast-feeding

- Women of childbearing potential & men who are sexually active and not willing/able to
use medically acceptable forms of contraception

- Patients with known potentially anaphylactic allergic reactions to
gadolinium-Diethylenetriaminepentaacetic Acid

- Patients who cannot undergo MRI or SPECT due to obesity or to having certain metal in
their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal
prostheses, joints, rods, or plates)

- Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord,
radiological evidence of multifocal disease, or leptomeningeal disease

- Severe, active comorbidity, including any of the following

- Unstable angina and/or congestive heart failure requiring hospitalization

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of study initiation

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy

- Known hepatic insufficiency resulting in clinical jaundice and/or coagulation
defects;

- Known Human Immunodeficiency Virus positive status

- Major medical illnesses or psychiatric impairments that, in the investigator's
opinion, will prevent administration or completion of protocol therapy

- Active connective tissue disorders, such as lupus or scleroderma that, in the
opinion of the treating physician, may put the patient at high risk for radiation
toxicity

- Co-medication that may interfere with study results; e.g. immuno-suppressive agents
other than corticosteroids;

- Prior, unrelated malignancy requiring current active treatment with the exception of
cervical carcinoma in situ and adequately treated basal cell or squamous cell
carcinoma of the skin;

- Patients are not permitted to have had any other conventional therapeutic intervention
other than steroids prior to enrollment outside of standard of care chemotherapy &
radiation therapy. Patients who receive previous inguinal lymph node dissection,
radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies will be excluded

- Current, recent (within 4 weeks of the administration of this study agent), or planned
participation in an experimental drug study

- Known history of autoimmune disease (with the exceptions of medically-controlled
hypothyroidism and Type I Diabetes Mellitus)