Glioblastoma, an aggressive and terminal form of brain cancer

Glioblastoma is a deadly form of cancer with a poor prognosis and no effective therapy. The average life expectancy after diagnosis ranges from 12 to 18 months. Current therapies that combine surgery, radiation therapy, and chemotherapy offer minimal clinical benefit. Similarly, recent advances in immunotherapy, such as immune checkpoint inhibitors, adoptive T-cell therapies, and cancer vaccines have had little impact on survival. Therefor there is a critical need to develop new drugs that can impact glioblastoma progression.

T cells can be engineered to selectively kill tumor cells

This groundbreaking approach in cancer immunotherapy involves genetically modifying a patient’s T cells to enhance their ability to recognize and destroy cancer cells. There are two types:

  1. Chimeric Antigen Receptor T cell (CAR-T) therapy

  2. T Cell Receptor (TCR) engineered T cell (TCR-T) therapy

CAR-T cells recognize tumor cell surface antigens independent of the Major Histocompatibility Complex (MHC), but generally do not target intracellular proteins. CAR-T cells are activated after binding to specific antigens on cancer cells, resulting in release of cytotoxic substances, primarily granzymes, into the cancer cell.

TCR-T cell therapy requires tumor antigens to be presented by MHC Class I, and can target intracellular derived tumor antigens (1). Intracellular proteins are cleaved into peptides, and are presented at the tumor cell surface by MHC molecules. TCR-T cells recognize the MHC-tumor peptide and kill the tumor cell.

These therapies have had great success in leukemias and lymphomas with more than half of patients experiencing long-term survival (2). However, application to solid tumors has been limited due to poor cell infiltration, ineffectiveness, and limited persistence.

Opportunity for TCR-T cell therapy of glioblastoma

An attractive TCR-T cell therapy for glioblastomas is Protein Tyrosine Phosphatase Receptor Type Z1 (PTPRZ1) expressed at high levels in glioblastomas, and is also involved in cancer proliferation, migration, invasiveness, angiogenesis and radioresistance (4).

Innovative approach, isolating T cells specific for the protein PTPRZ1 from vaccine treated glioblastoma patients and development of PTPRZ1-TCR-T

Chih et al. (3) in the laboratory of Dr. Lukas Bunse at the German Cancer Research Center in Heidelberg investigated PTPRZ1-reactive blood T cells from a glioblastoma patient who had been vaccinated with glioblastoma-associated peptides. T cells specific for tumor antigen PTPRZ1 from vaccinated glioblastoma patients were identified. TCR genes were isolated, and a unique sequence identified that is responsible for recognizing PTPRZ1 peptides (5). This TCR sequence was cloned and engineered into human T cells. TCR-T cells were produced to specifically target and kill glioblastoma cells expressing PTPRZ1. These TCR-T cells were termed PTPRZ1-TCR-T.

PTPRZ1-TCR-T kills human glioblastoma cells in vitro, preferentially those with cancer stem cell characteristics

PTPRZ1-TCR-T were capable of killing patient-derived human glioblastoma cells in vitro. Preferential killing was shown for tumor cells which have stem cell-like properties, such as tumor-initiating potential, enhanced proliferation and invasion, metastasis and therapeutic resistance.

PTPRZ1-TCR-T eliminate tumors in murine xenograft models of human glioblastoma

Human glioblastoma tumor cell line U87 was transplanted into immunodeficient mice (which allow for human T cells and human tumors to function and grow). PTPRZ1-TCR-T were injected at 5 and 16 days after tumor inoculation. Nearly complete tumor regression was observed in all treated mice at day 40 post inoculation.

Overcoming limitations due to MHC matching

TCR-T cell therapy depends on matching the MHC alleles of the donor T cells to the recipient patients MHC, in order to prevent graft rejection. In his case, the relevant MHC type is HLA-A02, with a frequency of 20.2% to 27.1% in human populations. Thus, engineered cells would be ineffective in patients who do not have that characteristic. However, HLA-A02 is a relatively common phenotype and the cell-based drug may find extensive use for treating glioblastoma.

Heading towards a cure, treating glioblastoma patients with PTPRZ1-TCR-T

The exciting news is that PTPRZ1-TCR-T produced positive preclinical results. Clinicians are initiating a phase I clinical trial to treat glioblastoma. The clinical study will assess safety of intravenous and intracerebroventricular PTPRZ1- TCR-T cell therapy in patients with recurrent glioblastoma. This study will be groundbreaking, being the first-in-human glioblastoma TCR-T cell therapy.

Rerefences

  1. Tsimberidou, et al. T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors. J. Hematol. Oncol. 14:102, 2021.
  2. Hirayama, et al. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T immunotherapy. Blood 134:636, 2019.
  3. Chih, et al, Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen. Nature Communications 16:1262, 2025.
  4. Lacore, et al. The glycoprotein M6a is associated with invasiveness and radioresistance of glioblastoma stem cells. Cells 11:2128, 2022.
  5. Wang, et al. Analysis of the CDR3 length repertoire and the diversity of T cell receptor a and b chains in swine CD4+ and D8+ T lymphocytes. Mol Med Rep 18:75,2017.

 

About Marin Biologic Laboratories (MarinBio)

 

Our Recent Publication/Meeting Presentation

American Society of Hematology (ASH) Annual Meeting 2024.

Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

Comprehensive Assay Solutions for In Vitro and Cell Based Potency Assays and Pharmacokinetics Studies- Our Expertise

With 30 years of expertise in cell culture, cell-based assays, and preclinical/clinical PK/PD analysis, we specialize in offering assay services essential for a wide variety of therapeutic drug development programs, preclinical studies, IND/BLA applications, and commercialization. Our comprehensive services include both preclinical non-GLP and GLP assays, as well as non-GMP and GMP assays, providing critical support throughout the entire development pipeline.

Watch the following video and explore our latest presentation on the development and validation of potency and pharmacokinetic (PK) assays for AAV vectors, highlighting innovative methodologies and industry-leading expertise.

 

 

Download the full presentation: Development of Custom Cell Based and In vitro Potency and Pharmacokinetics (PK) Assays for AAV vectors- Marin biologic Laboratories

Development of Cell-Based Potency Assays: Case Studies and Blogs from Marin Biologic Laboratories (MarinBio)

Drug Discovery & Development Assays Offered by Marin Biologic Laboratories (MarinBio)

Our Recent Blogs/Articles

 

Disclaimer: This information is intended solely for research purposes and does not serve as medical advice.