Clinical Study for the Safety and Therapeutic Efficacy of the AI-QMMM Designed TamavaqTM Personalised Vaccine in Patients With Newly Diagnosed Glioma.

Summary

Gliomas are a heterogeneous group of tumors arising from glial cells in the central nervous system and are associated with poor prognosis and significant morbidity. The most aggressive form, glioblastoma multiforme (GBM), remains particularly challenging to treat, often exhibiting resistance to conventional therapies such as chemotherapy and radiation. The average survival for patients with GBM is approximately 15 months, underscoring the urgent need for novel therapeutic strategies that can improve outcomes. Malignant gliomas are the most common primary brain cancer diagnosed and still carry a poor prognosis despite aggressive multimodal management. Despite the continued advances in immunotherapy for other cancer types, however, there remain no FDA approved immunotherapies for cancers such as glioblastoma. Neoantigen vaccines are a form of immunotherapy involving the use of DNA, mRNA, and proteins derived from non-synonymous mutations identified in patient tumor tissue samples to stimulate tumor-specific T-cell reactivity leading to enhance tumor targeting. Up to and including the current time, we have only nascent understandings, at the molecular and submolecular level, of how immunity is generated and maintained. As a result, we do not have fundamental mechanistic understandings of vaccine:antigen interactions, of vaccine-directed and initiated routes of immunity, nor how, through adjuvants and changes in our biologic environment (such as the intestinal microbiome), we might direct such immune responses. In particular, in the field of vaccinology we have few collaborations between biology, physics, and chemistry...or what has been termed "convergence science"...but particularly from physics and the field of quantum mechanics. Biophysics led to quantum biology and quantum immunology reflecting quantum dynamics within living systems and their evolution. Unfortunately, despite the seismic influence of immunotherapy on oncology today, there remain no FDA approved immunotherapies for GBM due to the lack of efficacy observed in several randomized clinical trials. The TAMAVAQ approaches enable a quantitative understanding of immune response kinetics following neoantigen-based peptide vaccine treatment. Insights gained from challenges can be used to design better vaccines and evaluate the potential candidate vaccines in silico. The TAMAVAQ models also can guide such decisions on treatment regimens such as dosing and infusion frequencies.

Eligibility

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. -

Conditions2

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