Vaccine Therapy for the Treatment of Newly Diagnosed Glioblastoma Multiforme

Dendritic cells (DC) are involved in activating, or turning-on, your body's immune system. Your immune system helps guard your body from germs, viruses, and other threats. Although dendritic cells are very strong, the number of them in the body is not high enough to cause a powerful immune response; therefore, more DC are made in a laboratory with cells collected from an individual's blood.

In this study, we will make a vaccine that we hope will educate immune cells to target the pp65 antigen, a type of immune marker in GBM, thus resulting in what we call the pp65 DC vaccine. Use of a vaccine that activates your immune system is a type of immunotherapy. It is hoped that by giving the pp65 DC vaccine as a shot under the skin, the immune system will be activated to attack tumor cells in the brain while leaving normal cells alone.

To see if the pp65 DC vaccine is effective for the treatment of GBM, subjects will be assigned to different treatment groups. Two groups of subjects will receive the pp65 DC vaccine and one group will receive a placebo.

• pp65-shLAMP DC with GM-CSF (Biological), also known as pp65-shLAMP mRNA DCs with GM-CSF
• unpulsed PBMC and saline (Biological), also known as Peripheral Blood Mononuclear Cells
• Td (Drug), also known as Tetanus and Diphtheria Toxoid: All subjects will receive a Td booster before study drug dose #1. Subjects in the experimental arms will receive Td skin prep before study drug doses #3, #6, and #9.
• Saline (Drug), also known as Normal Saline
• pp65-flLAMP DC with GM-CSF (Biological), also known as pp65-flLAMP mRNA DCs with GM-CSF

Primary outcomes

• Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3) [From date of first vaccine until the date of death, up to 48 months]: Kaplan-Meier survival curves and the log rank test will be used to characterize and compare OS in patients who received pp65-LAMP mRNA DC vaccine (Arms 1 and 2) and in control patients (Arm 3). OS will be defined as the time between first vaccination and death and will be censored at the last follow-up if death has not occurred.

Secondary outcomes

• Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3) [From date of first vaccine until time disease progression or death without prior progression/recurrence, up to 48 months]: Calculated as dated of first vaccine to date first progression/recurrence or death. Kaplan-Meier survival curves and the log rank test will be used to characterize and compare PFS in patients who received pp65-LAMP mRNA DC vaccine (Arms 1 and 2) and in control patients (Arm 3). PFS is defined as the time between first vaccination and first documentation of either disease progression/recurrence, or death without prior progression/recurrence.
• ELISPOT Assay (pp65) [baseline, post-vaccine #3]: Within patient changes from baseline to vaccine 3.
• Flow Cytometric Analysis (T Cell) [baseline, post-vaccine #3]: Percentage of circulating cellular subsets of T cells within PBMCs.
• Cytokine Array Analysis (IFN-g) [baseline, post-vaccine #3]: Change in concentration (pg/mL) of IFN-g as measured by multiplex array from Baseline (V1) to post-Vaccine #3.
• ELISPOT Assay (Actin) [baseline, post-vaccine #3]: Within patient changes from baseline to vaccine 3.
• Flow Cytometric Analysis (NK Cell) [baseline, post-vaccine #3]: Percentage of circulating cellular subsets of NK cells within PBMCs.
• Flow Cytometric Analysis (CD4.CD25 T Reg) [baseline, post-vaccine #3]: Percentage of circulating cellular subsets of CD4.CD25 T Reg within PBMCs.

Sex: All, ages: 18 Years to any

Abbreviated Inclusion Criteria:

To be assessed at study enrollment prior to standard of care chemo-radiation therapy:

* Age ≥ 18 years.
* Histopathologically proven newly-diagnosed de novo GBM (WHO Grade IV glioma)
* The tumor must have a supratentorial component.
* Must have undergone definitive surgical resection of tumor with less than approximately 3cm x 3cm residual enhancing tumor as product of longest perpendicular planes by MRI.
* Recovery from the effects of surgery, postoperative infection, and other complications.
* Diagnostic contrast-enhanced MRI or CT scan of the brain preoperatively and postoperatively.
* Karnofsky Performance Status of ≥ 70.
* Signed informed consent.
* For females of childbearing potential, negative serum pregnancy test.
* Women of childbearing potential and male participants must be willing to practice adequate contraception throughout the study and for at least 24 weeks after the last dose of study drug.

To be assessed prior to initiation of adjuvant TMZ:

* Must have completed RT (targeted total dose of 59.4-60.0 Gy over ≤ 7 weeks) and concomitant TMZ (targeted dose of 75mg/m2/d for ≤ 49 days) therapy without significant toxicity that persisted over 4 weeks.
* History \& physical with neurologic examination prior to initiation of adjuvant TMZ.
* For patients receiving steroids, daily dose must be ≤ 4 mg.
* CBC with differential with adequate bone marrow function.
* Adequate renal function.
* Adequate hepatic function.

Abbreviated Exclusion Criteria:

To be verified in order to randomize subject:

* Prior invasive malignancy unless disease free for ≥ 3 years.
* Metastases detected below the tentorium or beyond the cranial vault and leptomeningeal involvement.
* Recurrent or multifocal malignant gliomas.
* HIV, Hepatitis B, or Hepatitis C seropositive.
* Known active infection or immunosuppressive disease.
* Prior chemotherapy or radiosensitizers (including Gliadel wafers) for cancers of the head and neck region.
* Prior radiotherapy to the head or neck, resulting in overlap of radiation fields.
* Severe, active co-morbidity.
* Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the entire study period.
* Pregnant or lactating women.
* Prior allergic reaction to temozolomide, GM-CSF or Td.
* Prior history of brachial neuritis or Guillain-Barré syndrome.
* Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry.

To be assessed prior to initiation of adjuvant TMZ:

* Did not start radiation therapy and temozolomide within 7 weeks of surgery.
* Progression of disease as defined by modified RANO criteria.
* More than 45 days after completion of radiation therapy and temozolomide

Participant flow

Outcome results

• Comparison of Overall Survival (OS) Between the Active Treatment Group (Arms 1 and 2) and the Control Group (Arm 3) (Primary), Median, months: pp65-shLAMP DC With GM-CSF and Td (Arm 1) 16.9 (12.7 to 22.8); pp65-flLAMP DC With GM-CSF and Td (Arm 2) 16.2 (13.8 to 19.2); Unpulsed PBMC and Saline (Arm 3) 20.6 (15.4 to 30.2) (p 0.196)
• Comparison of Progression-free Survival Between the Active Treatment Group (Arms 1 and 2 Combined) and the Control Group (Arm 3) (Secondary), Median, months: pp65-shLAMP DC With GM-CSF and Td (Arm 1) 6.1 (3.9 to 11.0); Plus pp65-flLAMP DC With GM-CSF and Td (Arm 2) 6.4 (4.2 to 10.8); Unpulsed PBMC and Saline (Arm 3) 7.1 (3.9 to 14.8) (p 0.354)
• ELISPOT Assay (pp65) (Secondary), Mean, spot forming units (SFU): Arm 1: pp65-shLAMP DC With GM-CSF and Td 126.3 +/- 759.9; Arm 2: pp65-flLAMP DC With GM-CSF and Td 48.4 +/- 377.5; Arm 3: Unpulsed PBMC and Saline -162.7 +/- 1075.4 (p 0.038)
• Flow Cytometric Analysis (T Cell) (Secondary), Mean, percentage of PBMC: pp65-shLAMP DC With GM-CSF and Td (Arm 1) -0.1 +/- 11.1; pp65-flLAMP DC With GM-CSF and Td (Arm 2) 5.9 +/- 16.6; Unpulsed PBMC and Saline (Arm 3) 1.7 +/- 7.0
• Cytokine Array Analysis (IFN-g) (Secondary), Mean, pg/mL: pp65-shLAMP DC With GM-CSF and Td (Arm 1) -3.5 +/- 5.0; pp65-flLAMP DC With GM-CSF and Td (Arm 2) 3.3 +/- 17.7; Unpulsed PBMC and Saline (Arm 3) -1.7 +/- 10.0 (p 0.2)
• ELISPOT Assay (Actin) (Secondary), Mean, spot forming units (SFU): Arm 1: pp65-shLAMP DC With GM-CSF and Td 0.4 +/- 6.0; Arm 2: pp65-flLAMP DC With GM-CSF and Td -0.2 +/- 26.1; Arm 3: Unpulsed PBMC and Saline -0.4 +/- 9.4 (p 0.6)
• Flow Cytometric Analysis (NK Cell) (Secondary), Mean, percentage of PBMC: pp65-shLAMP DC With GM-CSF and Td (Arm 1) -1.3 +/- 11.1; pp65-flLAMP DC With GM-CSF and Td (Arm 2) 5.9 +/- 16.6; Unpulsed PBMC and Saline (Arm 3) 1.7 +/- 7.0
• Flow Cytometric Analysis (CD4.CD25 T Reg) (Secondary), Mean, percentage of PBMC: pp65-shLAMP DC With GM-CSF and Td (Arm 1) -0.1 +/- 4.3; pp65-flLAMP DC With GM-CSF and Td (Arm 2) 1.4 +/- 2.2; Unpulsed PBMC and Saline (Arm 3) -0.1 +/- 2.0 (p 0.13)

Adverse events

Time frame: AE collection began at the time of administration of vaccine #1 and continued until 30 days after the last dose of study drug, up to 13 months for each participant. All-cause mortality was assessed up to 48 months.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2024-10-07)
• Informed Consent Form (PDF, 2021-10-21)

• Duane Mitchell, MD, PhD, Study chair, University of Florida
• Maryam Rahman, MD, Principal investigator, University of Florida

NIH grants: R01CA175517