Clinical Trial Finder

Inclusion Criteria:

• - 1.

**Age**:

• - Patients must be aged 18 years or older.

• - signed inform consent; - patients with recurrent malignant glioma; have received surgery, radiotherapy, chemotherapy; - patients' tumor tissue should have a high mutation load(>10 TMB); be genetically unstable; at least have 10 neoantigens; - should be able to provide tumor tissue and peripheral blood for sequencing and flow cytometry analysis; - at least three months post last operation; one month after the completion of the last anti-drug therapy or radiotherapy; - have not received any immunotherapy; - at least have one measurable lesion; - KPS >60; - estimated survival > 3 months.

• - patients should have adequate organ and bone marrow function; 2.

**Diagnosis**:

• - Histologically confirmed diagnosis of glioma, including: - Glioblastoma multiforme (GBM, WHO grade IV) - Anaplastic astrocytoma (WHO grade III) - Diffuse astrocytoma (WHO grade II) - Other gliomas (e.g., oligodendroglioma, mixed glioma) confirmed by pathology.

3. **Measurable Disease**:

• - Presence of measurable disease, defined as at least one tumor lesion that can be accurately assessed by imaging techniques (e.g., MRI) according to RECIST criteria.

4. **Performance Status**:

• - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating that patients are fully active, restricted in physically strenuous activity, or unable to work but able to care for themselves.

5. **Adequate Organ Function**:

• - Laboratory results must indicate adequate organ function, including: - Hematological parameters: Hemoglobin ≥ 9 g/dL, white blood cell count ≥ 3,000 cells/mm³, platelet count ≥ 100,000 cells/mm³.

• - Liver function tests: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the upper limit of normal (ULN) (or ≤ 5 times the ULN if there is liver involvement).

• - Renal function: Serum creatinine ≤ 1.5 times the ULN or estimated glomerular filtration rate (eGFR) ≥ 60 mL/min.

6. **Informed Consent**:

• - Provision of written informed consent by the patient or their legally authorized representative, indicating understanding of the study procedures, potential risks, and benefits.

7. **No Prior Treatment with Certain Therapies**:

• - Patients must not have received prior treatment with immune checkpoint inhibitors or other experimental immunotherapies that may interfere with the study outcomes.

8. **Ability to Comply with Study Procedures**:

• - Patients must be able to comply with all study procedures, including follow-up visits and assessments, as determined by the investigator.

9. **No Significant Cognitive Impairment**:

• - Patients must not have significant cognitive impairment or psychiatric disorders that would compromise their ability to provide informed consent or adhere to the study protocol.

These inclusion criteria are designed to ensure that the study population for this glioma targeted personalized neoantigen vaccine clinical trial is suitable for participation, allowing for the collection of meaningful data regarding the safety and efficacy of the investigational treatment. By clearly defining eligibility, the trial aims to target patients who are most likely to benefit from this AI-QMMM inspired therapeutic approach.

Exclusion Criteria:

1. **Previous Treatments**:

• - Patients who have received prior treatment with immune checkpoint inhibitors, other cancer vaccines, or experimental immunotherapies that may interfere with the study outcomes.

2. **Active Autoimmune Diseases**:

• - Patients with active autoimmune diseases or chronic inflammatory conditions requiring systemic treatment (e.g., rheumatoid arthritis, lupus, multiple sclerosis).

3. **Pregnancy or Breastfeeding**:

• - Pregnant or breastfeeding women, as the effects of the vaccine on fetal development or breastfeeding infants are not yet established.

4. **Other Malignancies**:

• - Patients with any other malignancy within the past 5 years, except for non-melanoma skin cancer or localized prostate cancer that is not currently active.

5. **Uncontrolled Medical Conditions**:

• - Patients with uncontrolled medical conditions, including but not limited to: - Cardiovascular disease (e.g., recent myocardial infarction, severe heart failure).

• - Uncontrolled infections (e.g., HIV, active hepatitis B or C).

• - Severe chronic lung disease.

6. **Significant Cognitive Impairment**:

• - Patients with significant cognitive impairment or psychiatric disorders that would limit their ability to provide informed consent or comply with study procedures.

7. **Severe Allergies**:

• - Patients with known hypersensitivity or severe allergic reactions to any component of the vaccine formulation or adjuvants used in the study.

8. **Concurrent Participation in Other Clinical Trials**:

• - Patients currently participating in other clinical trials involving investigational drugs or therapies that may interfere with the study outcomes.

9. **History of Organ Transplant**:

• - Patients who have received an organ transplant that requires ongoing immunosuppressive therapy.

10. **Severe Comorbidities**:

• - Patients with severe comorbid conditions that, in the opinion of the investigator, may compromise the safety of the patient or interfere with the assessment of the study endpoints.

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Quantum Vaccinomics for the Generation of the TAMAVAQ personalized neoantigenic vaccines. The personalized neoantigen vaccines will be prepared based on the analysis of whole-exome sequencing (WES) and RNA-seq data generated from fresh-frozen tumours or tumours that will be available as formalin-fixed paraffin-embedded (FFPE) tissue, obtained at the time of diagnostic resection. WES of normal tissue will be generated from autologous PBMC DNA. Patient HLA allotype will be assessed using standard class I and class II PCR-based typing (BWH Tissue Typing Laboratory). Coding mutations will be identified and personal neoantigens will be predicted based on binding affinity analysis to individual HLA alleles using class I MHC binding prediction tools with a cut-off of predicted IC50 < 500 nM for selected epitopes. Quantum Circuit platforms for the identification of immunological quantum and design of TAMAVAQ's NeoVaccine consisted of Druggable Immunodominant and Immunogenic Neo-epitopic Peptides will be incorporated in this clinical study. Candidate and Prioritized Neo-epitopic Peptides are identified using systems biology integration of omics dataset combined with Big Data analytics and machine learning. Then, the immunodominant quantized peptide will be identified by using in silico algorithms and HLA epitope mapping and binding domains involved in each one Glioma Patient's Drug-DNA-Protein-protein interactions. This clinical trial provides an AI-QMMM method for the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens exploring their current status, inherent challenges, and clinical translation potential against Glioma medical conditions. Enhanced Targeted Therapy**:- The TAMAVAQ vaccine specifically targets neoantigens unique to glioma cells, potentially leading to a more effective immune response while sparing healthy cells. This specificity may reduce collateral damage associated with traditional cancer therapies. Immune System Activation**:The TAMAVAQ personalized vaccine is designed to stimulate the patient's immune system, enhancing its ability to recognize and attack glioma cells. This activation can lead to a more robust and sustained anti-tumor response. Potential for Long-term Remission**:- By training the immune system to identify and remember glioma cells, patients may achieve longer-lasting remission rates and a reduced likelihood of tumor recurrence compared to conventional therapies.**Reduction in Side Effects**:- Compared to traditional treatments such as chemotherapy and radiation, which often come with significant side effects, the TAMAVAQ personalized neoantigen vaccine may result in fewer adverse effects, thereby improving the patient's quality of life. Personalized Treatment Approach**:- Each TAMAVAQ vaccine is tailored to the individual patient's tumor profile, potentially increasing the efficacy of the treatment. This personalization allows for a more precise approach to therapy that aligns with the unique characteristics of each Glioma patient's cancer. Opportunities for Combination Therapies**:- The TAMAVAQ vaccine can potentially be used in conjunction with other treatments (e.g., checkpoint inhibitors, targeted therapies), enhancing overall treatment effectiveness and providing a multifaceted approach to combat glioma.**Real-time Monitoring and Adaptation**:- This clinical trial setting allows for continuous monitoring of patient responses, providing valuable data that can lead to adaptations in treatment strategies based on observed efficacy and safety profiles. Contribution to Scientific Knowledge**:- The TAMAVAQ trial can provide critical insights into the mechanisms of immune responses against gliomas, contributing to the broader understanding of cancer immunotherapy and paving the way for future treatments.**Potential for Broader Application**:Success in the glioma trial may lead to the development of similar personalized vaccines for other cancer types, expanding the impact of this innovative therapeutic approach.**Patient Empowerment and Engagement**:Participation in TAMAVAQ clinical trials often empowers patients by involving them in cutting-edge research, providing them with access to novel therapies and fostering a sense of hope in their treatment journey. This TAMAVAQ clinical trial holds substantial potential benefits, ranging from enhanced targeted therapy and immune activation to improved patient quality of life and contributions to scientific knowledge. As research progresses, it is essential to continue evaluating these benefits in conjunction with the associated risks to optimize treatment strategies for glioma patients.The development of the TAMAVAQ personalized vaccine represents a novel approach to glioma treatment. This analysis evaluates the potential risks and benefits associated with conducting a clinical trial for this innovative therapeutic strategy. This clinical trial aims to assess the safety, tolerability, and efficacy of a personalized neoantigenic vaccine designed for patients diagnosed with glioma. The TAMAVAQ study will involve identifying patient-specific neoantigens from tumor biopsies and formulating tailored vaccines to stimulate an immune response against glioma cells. Following surgery, patients will receive conventional radiation therapy administered at 180-200 cGy per fraction daily for five days per week to a total of approximately 60 Gy. Personalized neoantigen vaccines TAMAVAQ NeoVaccine will be prepared using information from fresh tumour and normal tissue obtained at the time of diagnostic resection, as described below. Algorithms and methods based on profiles of sequence motifs, quantitative matrices (QM), artificial neural networks (ANN), support vector machines (SVM), quantitative structure activity relationship (QSAR), T-cell major histocompatibility complex (MHC) class I binding prediction and molecular docking simulations among others will be combined and used in order to predict and design the TAMAVAQ NeoVaccine-Drug Product Neo-epitopes. Quantum chemical calculations (IBM Quantum Studio) will be used to predict the TAMAVAQ NeoVaccine-Drug Product's biological function and be applied to T-cell receptor interaction with TAMAVAQ NeoVaccine-Drug Product Peptide/MHC class

• I. A cluster of algorithms is proposed here using semi-empirical quantum mechanical methods for calculating peptide-MHC class I and II molecules binding energy for the rational design of T-cell TAMAVAQ NeoVaccine-Drug Product Neo-epitopes with application in cancer glioma vaccinology.

The vaccine will be administered subcutaneously at least seven to twelve weeks following completion of external beam radiotherapy. TAMAVAQ NeoVaccine-Drug Product will be applied before maintenance of TMZ cycles after completion of chemoradiation therapy (CRT). Beginning on day 14 before the first maintenance TMZ cycle, patients will receive 7 vaccinations with TAMAVAQ NeoVaccine drug products during 7 weeks. 20-200 μg per peptide per vial are used followed by two booster doses eight and sixteen weeks later. For each dose, vaccine will be administered within six hours of thawing in a non-rotating fashion to one of up to four extremities. Patients will be repeatedly vaccinated with TAMAVAQ NeoVaccine drug products beginning on day 33 of the 6 maintenance TMZ cycle. Patients will receive 9 vaccinations within 12 weeks. 20-400 μg per peptide per vial will be used. Concomitant medications deemed necessary for adequate patient care will be allowed, including concomitant corticosteroids for symptoms associated with cerebral oedema, but the study vaccine will be held for patients requiring more than 4 mg per day of dexamethasone within seven days of vaccine administration. Clinical assessment and monitoring will be delivered by using the RANO criteria and the Immunotherapy Response Assessment in the Neuro-Oncology criteria. Study Design.

• - Type**: Open-label, single-arm, multicenter clinical trial.

• - Phase**: Phases I & II.

• - Duration**: Approximately 24 months (including recruitment, treatment, and follow-up) Methodology.

Screening Phase (Month 1-2)**: Recruitment**: Patients will be recruited from participating medical centers and clinics. Informed Consent**: Obtain informed consent from eligible patients. Screening Assessments**: Conduct baseline assessments, including medical history, imaging, and laboratory tests to confirm eligibility. Vaccine Development Phase (Month 3-5)**: Tumor Biopsy**: Collect tumor samples from enrolled patients for sequencing and neoantigen identification. Neoantigen Identification**: Utilize computational algorithms and laboratory techniques to identify patient-specific neoantigens. Vaccine Formulation**: Develop personalized vaccines based on identified neoantigens tailored to each patient. Vaccination Phase (Month 6)**: -**Pre-Vaccination Assessments**: Conduct baseline assessments, including physical examinations and laboratory tests before vaccine administration.

• - TAMAVAQ Vaccine Administration**: Administer the TAMAVAQ personalized neoantigenic vaccine via subcutaneous or intradermal injection.

• - Immediate Post-Vaccination Monitoring**: Monitor patients for immediate side effects and adverse reactions for a specified period following vaccination.

Follow-Up Phase (Month 7-24)**: Regular Follow-Up Visits**: Schedule follow-up visits at regular intervals (e.g., every 4-6 weeks) to assess patient health, side effects, and immune response. Adverse Event Monitoring**: Continuously monitor and report any adverse events or serious adverse events to regulatory authorities.**Imaging and Laboratory Assessments**: Conduct imaging studies (e.g., MRI) and laboratory tests to evaluate treatment response and tumor status at designated follow-up intervals. Quality of Life Assessments**: Administer validated quality of life questionnaires at baseline and follow-up visits to assess the impact of AI-QMMM designed TAMAVAQ treatment.**Study Closure (Month 24)**: Final Patient Assessments**: Conduct final assessments for all participants to evaluate long-term outcomes and safety. Data Analysis and Reporting**: Analyze TAMAVAQ trial data and prepare reports for submission to regulatory authorities and publication in scientific journals. Feedback and Follow-Up**: Provide TAMAVAQ vaccinated participants with feedback on trial outcomes and offer continued follow-up care or access to alternative treatments as needed. Sample Size

• - Estimated based on expected effect size and power calculations, aiming for a target enrollment of approximately 50-140 patients to provide adequate statistical power for the primary and secondary endpoints.

Statistical Analysis.Descriptive Statistics**: To summarize demographic and baseline characteristics. Efficacy Analysis**: Kaplan-Meier survival curves for progression-free survival (PFS) and overall survival (OS). Adverse Events Analysis**: Frequency and severity of adverse events reported according to NCI CTCAE criteria.

Arms

Experimental: Experimental: personalized vaccine patients with recurrent malignant gliomas enrolled into this arm

Clinical event timeline and Dosing of TAMAVAQ VACCINES Clinical event timeline for the patients who received at least one vaccine dose of (20-200)μg TAMAVAQ NeoVaccine, will be calculated from surgery until time of death due to progressive disease. Median progression-free survival (PFS) and overall survival (OS) will be also calculated respectively. Among enrolled patients, a median of (110-145) somatic single-nucleotide variants per tumour (range, 75-158) will be tested with a median of (58-63) coding mutations per tumour (range, 32-93) using whole-exome sequencing, and the expression of a subset of genes will be confirmed by RNA sequencing (RNA-seq) analysis. These included mutations commonly observed in glioblastoma that affect PTEN, RB1 and EGFR. No IDH1 or IDH2 mutations will be also tested. A median of 60.5-70,8 HLA binders (range, 30-163) with a half-maximum inhibitory concentration (IC50) < 500 nM will be predicted per tumour.

Interventions

Biological: - Biological: personalized vaccine Based on genetic and transcriptional sequencing information, personalized peptide vaccines would be designed and produced;

TAMAVAQ Vaccine plus Poly-ICLC, cGAMP, Granulocyte-macrophage colony stimulating factor (GM-CSF), imiquimod, CpG oligodeoxynucleotides, saponins and monophosphoryl lipid A (MPLA) - TAMAVAQ VACCINE : Each one of our TAMAVAQ VACCINE is consisted of 1-35 (LIMPs, ASPs, and bEPTs) Personalised Synthetic Neoantigenic Peptides mixed with GBM TAAs, including MAGE-1, HER-2, gp100, AIM-2, TRP-2, EphA2,105 survivin50, IL13Rα2, heat-shock peptide protein complex-96 (HSPPC-96), and Smac-TLR7/8 peptides. - TAMAVAQ vaccine products are composed of 1-35 peptides from the Biogenea Pharmaceuticals Ltd warehouse. - TAMAVAQ vaccine will be applied before maintenance TMZ cycles after completion of chemoradiation therapy (CRT). Beginning on day 14 before the first maintenance TMZ cycle, patients will receive 7 vaccinations with TAMAVAC VACCINE