Multi-antigen T Cell Therapy for Brain Cancer

(REMIND Trial)

Overseen By Fahmida Hoq, MBBS, MS

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Catherine Bollard

Must not be taking: Immunosuppressive antibodies

Disqualifiers: Uncontrolled infections, HIV, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 42 days for initial monitoring, up to 1 year for additional infusions

33 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but there are specific requirements for stopping certain treatments. You must stop myelosuppressive chemotherapy at least 14 days before the TAA-T infusion, investigational agents 28 days prior, and biologic agents 7 days prior. Bevacizumab can be used if needed without a standard washout period.

What data supports the effectiveness of the treatment TAA-T for brain cancer?

Research shows that TAA-T cells, which are a type of immune cell therapy, have been effective and safe in treating other types of solid tumors and breast cancer. This suggests they might also be helpful for brain cancer, as they target specific proteins found on tumor cells, helping the immune system attack the cancer. ^{1 2 3 4 5}

Is multi-antigen T cell therapy safe for humans?

Research on multi-antigen T cell therapy, including trials for solid tumors and breast cancer, suggests it is potentially safe and non-toxic for humans. ^{1 2 4 6 7}

How is the TAA-T treatment for brain cancer different from other treatments?

TAA-T treatment is unique because it uses specially trained immune cells (T cells) that target multiple tumor-associated antigens, making it a potentially effective and less toxic option for brain cancer compared to traditional treatments. This approach involves expanding these T cells outside the body and then infusing them back into the patient to specifically attack cancer cells. ^{1 2 4 8 9}

What is the purpose of this trial?

This Phase I dose-escalation trial is designed to determine the safety and feasibility of rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs (Group A) or recurrent, progressive, or refractory non-brainstem CNS malignancies (Group B). Pediatric and adult patients who have high-risk CNS tumors known to typically have positivity for one or more Tumor Antigen Associated (TAA) (WT1, PRAME and/or Survivin) will be eligible. TAA-T will all be generated from patient peripheral blood mononuclear cells (PBMC). Group A patients (DIPG): The first TAA-T dose will be infused any time 14 days or more after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): The first TAA-T dose will be infused any time 14 days or more after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

Research Team

Eugene Hwang, MD

Principal Investigator

Children's National Health System

Eligibility Criteria

This trial is for pediatric and adult patients aged 6 months to 80 years with high-risk central nervous system (CNS) tumors, including DIPG, glioma, medulloblastoma, and other aggressive malignancies. Participants must have stable neurologic deficits if present, meet organ function requirements like adequate blood counts and liver function tests, not be pregnant or breastfeeding, agree to use contraception if applicable, and have recovered from prior treatments.

Inclusion Criteria

My blood counts and liver/kidney functions are within required ranges.

Available pre-trial tumor tissue (Optional for Group B patients, but highly encouraged)

My neurological symptoms have been stable for at least a week.

Exclusion Criteria

I have a history of cancer.

I have had a condition where my lymphocytes grow abnormally.

I do not have any infections that are currently uncontrolled.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiotherapy (Group A) / Conventional Therapy (Group B)

Completion of radiotherapy for Group A or conventional therapy for Group B before TAA-T infusion

Varies per patient

Treatment

Participants receive TAA-T infusions with dose escalation and monitoring for adverse events

42 days for initial monitoring, up to 1 year for additional infusions

Multiple visits for infusions and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• TAA-T

Trial Overview The trial is testing TAA-T cells made from the patient's own blood to fight brain tumors. It has two groups: one for new cases of a specific tumor in the brainstem after radiotherapy (Group A), another for recurrent or hard-to-treat CNS tumors after standard therapy (Group B). The safety and ability to make these personalized immune cells quickly are being studied.

Participant Groups

Group I: TAA-T Experimental Treatment 1 Intervention

Three different dosing schedules will be evaluated. Dose Level One: 2 x 107 cells/m2 Dose Level Two: 4 x 107 cells/m2 Dose Level Three: 8 x 107 cells/m2 Group A patients (DIPG): The first TAA-T dose will be infused any time more than or equal to 14 days after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time more than or equal to 14 days after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria. Ideally, patients should not receive other systemic antineoplastic agents for at least 42 days after the infusion of TAA-T, although such treatment may be added if deemed critical for patient care by the attending physician.

Who Is Running the Clinical Trial?

Catherine Bollard

Lead Sponsor

Trials

13

Recruited

290+

Children's National Research Institute

Collaborator

Trials

227

Recruited

258,000+

Findings from Research

In a first-in-human trial involving 15 patients with relapsed or refractory solid tumors, tumor-associated antigen cytotoxic T cells (TAA-Ts) were administered safely without any dose-limiting toxicities, demonstrating a promising new therapeutic approach.

Of the evaluable patients, 73% showed stable disease or better at day 45 post-infusion, with 6 patients remaining progression-free for a median of 13.9 months, indicating that TAA-Ts can effectively stabilize disease and prolong time to progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. Hont, AB., Cruz, CR., Ulrey, R., et al.[2020]

Co-administering tumor-associated antigen (TAA)-specific CD8+ T cells with TH1 polarized CD4+ T cells enhances the recruitment of these effector cells to brain tumors, which is crucial for effective immunotherapy.

Interestingly, while TH1 polarization improves initial recruitment, it is not necessary for the long-term therapeutic success of combined CD4+ and CD8+ T cell transfer, suggesting flexibility in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Getting by with a little help from the right CD4+ T cells. Hoepner, S., Walker, PR.[2021]

Recombinant monoclonal antibodies (MAbs) are becoming important in cancer therapy, especially when used alongside traditional anti-cancer drugs, enhancing treatment effectiveness.

Combining antibody therapy with toxins or radioisotopes, and developing immune cells like cytotoxic T-lymphocytes (CTLs) or natural killer (NK) cells that target tumor-associated antigens (TAAs), could significantly improve cancer immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible applications of antibodies or their genes in cancer therapy. Kuroki, M., Huang, J., Shibaguchi, H., et al.[2007]

In a first-in-human trial involving 10 heavily pre-treated patients with relapsed or metastatic breast cancer, multi-antigen-targeted T cells (multiTAA-T) were well tolerated with no treatment-related toxicities, indicating a promising safety profile for this therapy.

One patient experienced prolonged disease stabilization for 5 months, which was linked to the in vivo expansion and persistence of T cells targeting specific tumor antigens, along with evidence of broader immune activation against non-targeted tumor antigens in 7 out of 10 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer. Hoyos, V., Vasileiou, S., Kuvalekar, M., et al.[2022]

Human T cells can be genetically modified to express tumor-associated antigens, making them potential candidates for effective antigen-presenting cells in cancer immunotherapy.

The successful induction of tumor-specific T cell immune responses requires the activation of T cells using CD3/CD28 antibodies along with proinflammatory cytokines like IL-7 and IL-12, highlighting the importance of these components in developing cellular cancer vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modification of T lymphocytes to express tumor antigens. Foster, AE., Song, XT.[2021]

MDM2-specific T cells can survive in the body despite being exposed to normal tissue expression, but they struggle to proliferate and function effectively, leading to high rates of cell death when stimulated by their target antigen.

Cytokines like IL-2 and IL-15 can help improve the survival and function of these T cells, but they do not restore their full effectiveness, indicating potential challenges for immunotherapy targeting common tumor-associated antigens like MDM2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. Bendle, GM., Xue, SA., Holler, A., et al.[2022]

Tumor-associated antigen-specific cytotoxic T lymphocytes (TAA-CTL) were safely generated and infused into patients with multiple myeloma and non-Hodgkin lymphoma, with no significant adverse reactions reported during the treatment.

In a small group of 7 patients, TAA-CTL therapy showed promising efficacy, as 5 patients experienced positive clinical effects, and an increase in specific immune responses was observed 2-3 weeks post-infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Research of Dendritic Cell-Mediated Tumor-Associated Antigen-Specific Cytotoxic T Lymphocytes in the Treatment of Multiple Myeloma and Non-Hodgkin Lymphoma]. Li, XH., Xue, L., Xu, H., et al.[2020]

In a study involving 15 patients with recurrent astrocytoma, researchers successfully generated and expanded tumor-specific T cells from patients' blood after immunization with their own tumor cells, demonstrating the feasibility of this approach.

The intravenous transfer of these stimulated T cells was well-tolerated with limited toxicity, paving the way for future controlled studies to evaluate the anti-tumor effects of this immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma. Holladay, FP., Heitz-Turner, T., Bayer, WL., et al.[2019]

Adoptive transfer of ex vivo activated T lymphocytes from tumor-draining lymph nodes has shown effectiveness in treating experimental brain tumors, requiring both CD4 and CD8 T cells for optimal tumor regression.

A phase I clinical trial is underway to evaluate this T cell therapy for malignant astrocytomas, highlighting its potential as a targeted immunotherapy for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of intracranial tumors by systemic transfer of tumor-draining lymph node cells (Review). Plautz, G., Shu, S.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Getting by with a little help from the right CD4+ T cells. [2021]

3. Greece pubmed.ncbi.nlm.nih.gov

Possible applications of antibodies or their genes in cancer therapy. [2007]

4. England pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Modification of T lymphocytes to express tumor antigens. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. [2022]

7. China pubmed.ncbi.nlm.nih.gov

[Clinical Research of Dendritic Cell-Mediated Tumor-Associated Antigen-Specific Cytotoxic T Lymphocytes in the Treatment of Multiple Myeloma and Non-Hodgkin Lymphoma]. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma. [2019]

9. Greece pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of intracranial tumors by systemic transfer of tumor-draining lymph node cells (Review). [2019]