CBC Complete Blood Count and Differential. Is a test that reveals information about blood (I.e, White Blood Cells (WBC), Red Blood Cells (RBC), Platelets, etc.)
serum hCG. Is a blood test to check the hormone protein levels. Human Chorionic Gonadotropin (hCG) is a hormone produced during pregnancy.
Lactate Dehydrogenase (LDH)
IXRS. interactive voice/web-response system used for randomizing a patient. Upon receipt of the Sponsor's confirmation of the patient's eligibility, the site will call or log onto the IXRS to randomize a patient into the trial.
eCRF Electronic Case Report File. The patient is observed for 2hours after administration of each injection with vitals (heart rate, respiration rate, and blood pressure) taken pre-injection and every 30 ± 5 minutes and only recorded
(as AEs) if considered clinically significant.
All data over the course of the study is collected and recorded in the eCRF
Adverse Events (AE)
Serious Adverse Events (SAE)
Quality of Life (QoL)
KPS Karnofsky Performance Score:
All patients must have a Karnofsky Performance Score (KPS) of ≥70, ≥8 week life expectancy, no other prior malignancy within the last 5 years, and no active infections.
In this trial KARNOFSKY PERFORMANCE SCALE Point Description is:
100 Normal, no complaints, no evidence of disease
90 Able to carry on normal activity
80 Normal activity with effort, some signs or symptoms of disease
70 Cares for self, unable to carry on normal activity or do active work
60 Requires occasional assistance but is able to care for most of his/her needs
50 Requires considerable assistance and frequent medical care
40 Disabled, requires special care and assistance
30 Severely disabled, hospitalization indicated, death not imminent
20 Very sick, hospitalization necessary, active support treatment necessary
10 Moribund, fatal processes progressing rapidly
0 Dead
Peripheral Blood Mononuclear Cells (PBMCs)
DCs are generated from adherent PBMC cultured in the presence of IL-4 and GM-CSF
Good Manufacturing Practice (GMP) facility ?
distilled Phosphate Buffer Saline (dPBS)?
Central Nervous System (CNS) ?
Magnetic Resonance Imaging (MRI) ?
Positron Emission Tomography (PET) scan imaging technique ?
Disease progression is assessed by MRI, including T1, T2 and FLAIR sequences. Perfusion MRI.
T2 - weighted Dynamic Susceptibility-weighted Contrast–enhanced (DSC) imaging and the derived rCBV ?
relative Cerebral Blood Volume (rCBV)
DSC perfusion MRI:
DWI perfusion MRI:
Tumor volumes were estimated by adding all regions of interest (ROI) of the tumor and correlated to postmortem histological findings to understand the molecular mechanism of tumor development in vivo.
Some advanced MRI techniques have shown promising results of distinguishing posttreatment necrosis from tumor progression and pseudoprogression, including MR spectroscopy (higher Cho/Cr and Cho/NAA ratios), MR perfusion imaging, and diffusion-weighted MRI, namely, relative cerebral blood volume (rCBV) as an imaging biomarker for increased neoangiogenesis and apparent diffusion coefficient (ADC) value as an imaging biomarker of increased cellular density.?
Statistical Analysis Plan (SAP)
Intra-Operative MRI (iMRI or ioMRI) - imaging guidance MRI that is used during glioma surgery to maximize extent of Resection. Before they close a patient up, they take a scan to see if there is any more tumor to remove. Brain shifts during surgery, and before this machine tumor was left behind.
Rapidprogression Disease (rPD) or (ePD)
Psuedoprogression Disease (PsPD) or (pPD) or (PP)?
Competent Authorities (CA) ?
Institutional Review Board (IRB)?
Independent Ethics Committee (IEC)
Informed Consent Health (ICH) Guidelines.
DMC Data Monitoring Committee
IDMC Independent DMC
Clinical Research Organization (CRO)
Principal Investigator (PI)?
IS Independent Statistician (IS)
ETHICAL CONSIDERATIONS:
The investigator agrees to conduct this study in accordance with applicable United
States FDA clinical trial regulations and guidelines, applicable United States FDA
clinical trial regulations and guidelines, the ICH (E6) GCP guidelines, the European
Union Directive 2001/20/EC for clinical trials conducted in the European Union, the
IRB/EC and local legal requirements and with the Declaration of Helsinki (1989). The
investigator will conduct all aspects of this study in accordance with all national,
state, and local laws of the applicable regulatory agencies.
?
CMP Comprehensive metabolic panel. includes electrolyte balance, and hepatic and renal
functions.?
EOT End of Treatment (refers to off treatment and tracked for OS)
EOS End of Study
ITT Intent to Treat (refers to Ph II patient population)
GTR Gross Total Resection
NTR Near Total Resection
PR Partial Resection ?
PFS Progression Free Survival (Primary Endpoint)
OS Overall Survival (Secondary Endpoint)
TTP Time to Progression (Tertiary Endpoint)
DFS. Disease-Free Survival?
RECIST Response Evaluation Criteria In Solid Tumors ?
Response Assessment in Neuro-Oncology (RANO) criteria.?
Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria ?
ORR Overall Response Rate
CR Complete Response
PR Partial Response
PD Progressive Disease
SD Stable Disease
NED No Evidence of Disease
BL. Baseline
GBM glioblastoma multiforme.
BBB Blood Brain Barrier.
Radiation (XRT) or Radiotherapy (RT)?
TMZ Temozolomide (chemotherapy drug official name) a.k.a Temodar (registered retail drug name)
radiotherapy/temozolomide (RT/TMZ) ?
Chemotherapy agents that can be used upon progression consisting of temozolomide, procarbazine, carboplatin, vincristine,1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), thalidomide, irinotecan, isotretinoin, imatinib, etoposide, and combinations thereof.?
Gliadel wafers: a wafer loaded with BCNU drug and implanted in tumor bed brain cavity, thus bypasses the need to get through the BBB . BCNU cytotoxic drug diffuses out of the wafer over time and was approved for the use of recurrent GBM as it improved median survival eight weeks. ?
Peripheral Blood Lymphocytes (PBLs) ?
Autologous Tumor Lysate (ATL)?
Dendritic Cells (DC or DCs)?
Immature Dendritic Cells (iDCs)
Mature Dendritic Cells (mDCs)?
Natural Killer DCs (NKDCs)
Interferon-producing Killer DCs (IKDCs)
DCs are essentially the master regulators of immune responses, and they are the most potent APC
Antigen-Presenting Cell (APC)
Major Histocompatibility Complex (MHC) Class I and II eliciting a multivalent CD8+ and CD4+ antitumor response. ?
Stimulating MHC Class II recruits Helper T cell epitopes or CD4+ (T helper (Th) cells) ?
Stimulating MHC Class I recruits Killer T cells or CD8+ (cytotoxic lymphocytes) ?
Absolute Lymphocyte Counts (ALCs)
Absolute Neutrophil Counts (ANCs)
Tumor Infiltrating Lymphocytes (TILs)?
Human Leukocyte Antigen (HLA)-A2-restricted means targeting HLA-A2 positive patients, to benefit from treatment. (Peptide vaccines).
Whole Tumor Cell Lysate (WTCL) treatment is suitable for all cancer patients regardless of their HLA type. (DCVax-L)
GBM ATL are broken down into antigen fragments and pulsed with adjuvants to update antigens and induce maturation ?
Interferon ? (IFN?) ?
Bacillus-Calmette-Guerrin (BCG) is a a bacterium that expresses an immunogenic portion of the polypeptide on its cell surface or secretes such an epitope.?
BCG it is an bacterium adjuvant used in pulsing tumor antigen with DCs.
When DCs are pulsed with a soluble antigen, including human tumor antigen or tissue specific antigens with an adjuvant such as BCG, enhancement of MHC-class I presentation occurs and correspondingly, activates a higher percentage of CD8+ T cells when compared to individuals administered the antigen alone.
Human Interleukin-4 (IL-4) a recombinant used during the manufacturing process to monocytes-derived DC into iDC.?
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) - recombinant that is used during the manufacturing process to enhance the recruitment of DCs to the vaccination site. It is also used to monocytes-derived DC into iDC.
RPMI is a solution that cells were cultured in and used during the manufacturing process.
Toll-Like Receptors (TLRs)
Pathogen-Associated Molecular Patterns (PAMPs)
Damage-Associated Molecular Patterns (DAMPs).
DCs in general possess a diverse repertoire of surface receptors (and intracellular receptors) that help them in environmental sensing and to carry out “at will” rapid innate immunity-related functions. Such receptors include various scavenging or phagocytic receptors like CD91, integrins, CD36 (aiding in phagocytosis and clearance of target entities), surface pattern recognition receptors (PRRs) like toll-like receptors (TLRs), and intracellular PRRs like NOD-like receptors (NLRs). DC-based PRRs help in detection (and subsequent DC stimulation) of danger signals like pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs).
Imiquimod is TLR-4 adjuvant cream that was used at booster stage in Phase I/II in some patients. It is also in UCLA Phase II testing (recruitment closed) to see best combination (DCVax-L no adjuvant verses DCVax-L + Imiquimod cream verses DCVax-L + Poly ICLC cream). Primary Endpoint Results Due next Sept. There is no cream being used in DCVax-L Phase III.
Poly ICLC is a TLR-9 Adjuvant injection that was used at booster stage in Phase I/II in some other patients. It is also in UCLA Phase II testing (recruitment closed) to see best combination (DCVax-L no adjuvant verses DCVax-L + Imiquimod cream verses DCVax-L + Poly ICLC cream). Primary Endpoint Results Due next Sept. There is no cream being used in DCVax-L Phase III.??
Transforming Growth Factor (TGF)-ß that can inhibit anti-tumor responses and facilitate T Regulatory (Treg) ?
Heat-Shock Proteins (HSPs)
Platelet Derived Growth Factor
(PDGF)?
Epidermal Growth Factor Receptor (EGFR)?
EGFR mutation ?
T Regulatory Cells (Treg)
FOXP3+ (Tregs.)?
Programmed Cell Death (PD-1)?
Programmed Cell Death Ligands, PD-L1 or PD-L2?
Monoclonal Antibody (mAb)
Delayed-Type Hypersensitivity (DTH) reaction.
Tangient Flow Filtration (TFF) - patented automation method to get precursor DCs
National Clinical Trial (NCT) registry?
O(6)-methylguanine-DNA methyltransferase (MGMT) ?
O6-Methylguanine DNA MGMT Promoter:
The methylation status of the MGMT promoter has been shown to be a potent prognostic factor in patients with GBM; cells that are deficient in MGMT have shown an increased sensitivity to Temodar (TMZ) chemotherapy. Patients with low MGMT expression (due to methylation of the promoter) benefit more from adjuvant TMZ. TMZ chemotherapy enhances radiation response in MGMT-methylated glioblastoma cells by enhancing double-strand DNA damage, a critical factor underlying radiation-induced cell death. Effective treatment, such as TMZ concomitant with radiotherapy, can lead to the disruption of the blood–brain barrier, allowing the passage of chemotherapeutic agents and thus enhancing their activity.
mMGMT is low MGMT expression or MGMT-methylated promoter status (TMZ responsive)
unMGMT is high MGMT expression or MGMT un-methylation promoter status (not TMZ chemo responsive, high likelihood to be rapid progression patients)
Genetic and molecular changes have also been associated with pseudoprogression. ?
Isocitrate Dehydrogenase 1 (IDH1) mutation
p53 over expression
Only certain genes can be mutated in ways which make the cells possessing them cancerous. Mutated genes that have this effect are called "cellular oncogenes", & the normal versions "proto-oncogenes".
The names given to oncogenes usually consist of 3 letters. For example, src, ras, sis, myc and mos. To distinguish between viral genes and their host equivalents, the viral forms are called "viral oncogenes" (e.g. v-src, v-sis etc.) as opposed to "cellular oncogenes" (c-src, c-sis, c-mos etc.). These normal equivalents are also called "proto-oncogenes", but this terminology is more appropriate to the situation where the cancer has been caused by somatic mutation, rather than by duplication or over-expression.?
"Anti-oncogenes" (also called "tumor suppressor genes") are a special type of oncogene.The distinction is between dominant and a recessive mutations, with most oncogenes being dominant, and anti-oncogenes being recessive. In other words, it is the under-activity of the anti-oncogenes that makes the cells possessing them cancerous, rather than over-activity having this result, as is the case with the great majority of oncogenes. Both copies of such an anti-oncogene gene (i.e. the copies on both of the 2 sets of chromosomes) have to be inactivated in order for the cell to become cancerous.?
By far the best-studied anti-oncogene is the one called rb (or rb-1), which causes retinoblastoma in humans. This runs in families and results in eventual blindness due to the formation of multiple tumors in both eyes (in the person's 30s or 40s). Such persons lack a functional rb gene on one of their two sets of chromosomes, so that any retinal cell which undergoes a sufficiently deleterious mutation in the remaining functional copy will give rise to a clone of tumor cells.?
More examples of oncogenes:
sis: Codes for a form of PDGF (Platelet Derived Growth Factor). PDGF normally serves as a cell-to-cell signal, secreted by platelets and diffusing to other cells such as fibroblasts and smooth muscle cells, which it stimulates to grow and crawl about. If a cell produces its own form of PDGF, it behaves as if it were being constantly exposed to high concentrations of external PDGF; in other words, it stimulates its own growth and locomotion without limit. ?
erbB: Codes for an abnormal version of the membrane receptor for the extracellular protein called epidermal growth factor. This form of the receptor behaves as if it were constantly bound to molecules of its growth factor, thus constantly sending a false signal stimulating cell growth. A similar oncogene, called erbB-2 seems (based on its base sequence) to code for a receptor for some other (still undiscovered) growth factor. It is found in amplified form in about one fourth of all human breast and ovarian cancers!
ras:The function of its normal equivalent protein is to relay and amplify stimulatory signals, such as those from growth factor receptors. It binds a molecule of GTP whenever it is itself stimulated. It then relays stimulatory signals and continues to do so until its GTP is hydrolysed to GDP. Certain specific amino acid substitutions eliminate this protein's ability to hydrolyze bound GTP, however, so that it remains permanently in its "on" state, constantly "relaying" non-existent signals for the cell to grow and divide. Such mutations of this one oncogene are believed to be responsible for no fewer than one fifth of all human cancers, including up to half of colon carcinomas, and 90% of cancers of the pancreas! (Although note that several different ras genes are known.) Out of 25 average people, ras will kill one of them!
src: Codes for a protein that spontaneously becomes concentrated on the inside surface of the plasma membrane, especially at the sites of cell-substratum adhesion. This protein is an enzyme (a tyrosine kinase) whose effect is to catalyze the covalent bonding of phosphate groups onto the hydroxyl group of tyrosine amino acid residues of proteins. ?
myc:Codes for a nuclear protein whose normal function seems to be as some kind of a transcription factor promoting cell growth. For example, when a normal cell is stimulated to grow and divide (for example, by exposure to PDGF), then the c-myc gene product (protein) temporarily increases in concentration; conversely, this gene normally becomes inactive in non-mitotic cell types. Many human cancers have been shown to have undergone amplification of the c-myc gene (often about 10 copies of the gene). The progression of cancerous cells to ever more and more aggressive states is frequently traceable to further amplification of the myc gene.
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bcl-2:This name stands for B cell lymphoma and the protein for which this gene codes seems to have the normal function of inhibiting the spontaneous death of B-lymphocytes. ?
p53 is sometimes considered an anti-oncogene, in that cancer can result from decreases in its expression. It was first discovered as a cancer antigen; because some cancers produced so much of it, and perhaps also because it was present in a modified mutated form, antibodies were made against it. Its normal function is part of cell cycle control mechanisms for detecting damage to DNA (for example by X-rays) and serving to block the cell cycle at the onset of DNA synthesis until the damage can be repaired. It also has some effect on controlling apoptosis, acting in combination with myc genes.
