Immunotherapy for Solid Cancers

(REST Trial)

Overseen By Fahmida Hoq, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's National Research Institute

Must not be taking: Steroids, ATG, Campath

Disqualifiers: Uncontrolled infections, Active HIV, GVHD, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 6 months

28 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on steroids, the dose must be less than 0.5 mg/kg/day of prednisone (or equivalent). Also, you should not have received certain immunosuppressive treatments like ATG or Campath within 28 days before the cell infusion.

What data supports the effectiveness of the treatment Tumor associated antigen lymphocytes (TAA-CTL) for solid cancers?

Research shows that tumor-associated antigen-specific cytotoxic T lymphocytes (TAA-CTL) have been explored as a potentially effective and non-toxic treatment for relapsed or hard-to-treat solid tumors. These T cells are designed to target specific proteins found on cancer cells, and early studies suggest they could be a promising option for boosting the immune system's ability to fight cancer. ^{1 2 3 4 5}

Is immunotherapy using tumor-associated antigen lymphocytes (TAA-CTL) safe for humans?

In a study involving patients with relapsed or refractory solid tumors, TAA-CTLs were found to be a potentially nontoxic treatment option. Another study using personalized TAA vaccines in solid tumor patients reported no severe adverse events, suggesting that this type of immunotherapy is generally safe. ^{1 2 6 7 8}

How is the treatment Tumor associated antigen lymphocytes (TAA-CTL) different from other treatments for solid cancers?

This treatment uses special immune cells called cytotoxic T lymphocytes (CTLs) that are trained to recognize and attack specific markers (antigens) on cancer cells, making it a targeted and potentially less toxic option compared to traditional treatments like chemotherapy. ^{1 2 9 10 11}

What is the purpose of this trial?

Patients with high-risk solid tumors, those that are refractory to standard up front therapy or relapse after completion of therapy, have a very poor prognosis despite attempts to induce remission with salvage regimen. Novel therapies are critical for this patient population with high-risk cancer. The ability of tumors to be recognized and lysed by the immune system offers a unique opportunity to aid in tumor eradication by expanding and activating these anti-tumor cells. Through this ability to harness sophisticated and specific immunotherapy, residual or relapsed disease that is resistant to chemotherapy and/or radiotherapy could be eradicated. Prior studies have suggested both safety of expanded specific T cells and efficacy in the setting of melanoma, lymphoma or viral eradication. While this therapy has previously been limited by the versatility of the tumor to down-regulate antigens and evade a single immune-target, the use of multi-antigen specific T cells may permit better and more durable anti-tumor immunity. Thus, the investigators propose to infuse these specific multi-antigen anti-tumor T lymphocytes into patients with high risk solid tumors. This trial will be conducted to demonstrate safety of these cells and generate efficacy and biology data that may be important for future studies that may enhance tumor immunotherapy.

Eligibility Criteria

This trial is for people aged 6 months to 60 years with high-risk solid tumors like Ewing sarcoma or adenocarcinoma, who have either not responded to standard treatments or whose cancer has returned. Participants need a minimum level of immune cells and organ function, must not be pregnant or breastfeeding, agree to use contraception if applicable, and cannot have uncontrolled infections or recent immunotherapy.

Inclusion Criteria

I (or my guardian) can understand and agree to the study's terms.

Bilirubin ≤ 2.5 mg/dL

Absolute lymphocyte count (ALC) greater than 1000/µL

Exclusion Criteria

I do not have any infections that are currently uncontrolled.

Patients with active HIV

Pregnant or lactating females

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TAA-CTL infusions with dose escalation to determine the maximum tolerated dose

Approximately 6 months

Multiple visits for infusions and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Extension

Participants with stable disease or better may receive additional doses of CTLs at 28-day intervals

Up to 6 months

Treatment Details

Interventions

• Tumor associated antigen lymphocytes (TAA-CTL)

Trial Overview The study tests the safety and potential effectiveness of TAA-CTLs—immune cells trained to target multiple tumor-associated antigens—in patients with tough-to-treat solid tumors. The goal is to see if these specialized T cells can help fight off cancers that haven't responded well to other treatments.

Participant Groups

Group I: Group B Experimental Treatment 1 Intervention

Group B includes patients who have undergone conventional (standard) therapy which does not include an allogeneic HSCT. Within group B, a cohort of patients with relapsed or refractory Wilms tumor will be enrolled and receive a lymphodepleting chemotherapy regimen followed by TAA-T. Group B patients (no prior allogeneic HSCT): TAA-T will be infused any time \>1 week after completing most recent course of conventional (non-investigational) therapy for their disease. Patients receiving lymphodepletion will be \>2 weeks from most recent course of conventional therapy and have nadired and recovered before beginning protocol therapy.

Group II: Group A Experimental Treatment 1 Intervention

Group A includes patients who have undergone an allogeneic hematopoietic stem cell transplant (HSCT) as part of their prior therapy. Group A patients (post allogeneic HSCT): TAA-T will be infused any time after neutrophil engraftment post-HSCT or day 30, whichever comes first.

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

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]

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]

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]

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 study involving 12 chronic lymphocytic leukemia (CLL) patients, MDM2-specific T cells were successfully generated in 7 patients, demonstrating the potential of MDM2 as a tumor-associated antigen for immunotherapy.

The study found that the ability of antigen-presenting cells (APCs) to secrete IFN-gamma was a key factor in generating effective MDM2-specific T cells, highlighting the importance of APC functionality in developing targeted immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes. Mayr, C., Bund, D., Schlee, M., et al.[2020]

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. 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]

3. Germany pubmed.ncbi.nlm.nih.gov

Tumor-associated antigen profiling in breast and ovarian cancer: mRNA, protein or T cell recognition? [2020]

4. Germany pubmed.ncbi.nlm.nih.gov

The role of CD8(+) T cells in immune responses to colorectal cancer. [2004]

5. Germany pubmed.ncbi.nlm.nih.gov

A listing of human tumor antigens recognized by T cells: March 2004 update. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients. [2021]

7. 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]

8. Greece pubmed.ncbi.nlm.nih.gov

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

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

Immunotherapy using allogeneic squamous cell tumor-dendritic cell fusion hybrids. [2010]

10. Netherlands pubmed.ncbi.nlm.nih.gov

MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes. [2020]

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

Co-stimulatory tumor necrosis factor ligands as adjuvants for the development of subunit-based anticancer vaccines. [2021]