attIL12 T-Cell Therapy for Sarcoma

Overseen By John Livingston, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids

Disqualifiers: Autoimmune disease, CNS metastases, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 months

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called attIL2-T cell therapy, a type of immunotherapy, for individuals with soft tissue or bone sarcomas, which are types of cancer. The goal is to determine the optimal dose and assess its effectiveness in controlling the disease. The trial begins by testing different doses and later focuses on osteosarcoma, a specific type of bone cancer. It suits those who have previously tried other sarcoma treatments without success and have a form of the disease that cannot be surgically removed. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment at the time of leukapheresis or attIL12 T cell infusion. Standard of care anti-cancer therapy is allowed after leukapheresis but before starting cyclophosphamide. Non-cancer-related medications like insulin for diabetes are acceptable.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment at the time of leukapheresis or attIL12 T cell infusion. You can continue using hormones for non-cancer-related conditions like insulin for diabetes.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that attIL12-T cell therapy appears promising in early studies. It targets specific tumor features, offering a focused treatment option. Previous research found it safe for patients with osteosarcoma, a type of bone cancer.

As a Phase 1 trial, the main goal is to determine a safe dose, so the treatment's safety is under close observation. Earlier research suggests that patients generally tolerate the treatment well. The study team carefully monitors any side effects or adverse events to ensure participant safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sarcoma?

Unlike the standard treatments for sarcoma, which often include surgery, chemotherapy, and radiation, attIL2-T cell therapy is an innovative approach that harnesses the power of the immune system to fight cancer. This therapy uses genetically modified T-cells that are designed to target and destroy cancer cells more effectively. Researchers are excited about attIL2 because it offers a targeted action, potentially leading to fewer side effects and more precise treatment compared to conventional methods. By directly engaging the body's own immune response, this therapy holds promise for improved outcomes in patients with sarcoma.

What evidence suggests that attIL2-T cell therapy might be an effective treatment for sarcoma?

Research has shown that attIL12-T cells, which participants in this trial will receive, could help treat sarcomas, cancers affecting bones and soft tissues. In earlier studies, these specially modified cells demonstrated strong effects against tumors in osteosarcoma models, a type of bone cancer. The treatment enhances the immune system's ability to fight cancer cells, increasing the production of a key protein called IFNγ, which helps slow tumor growth. Early research also suggests that attIL12-T cells might remember and attack cancer cells over time, with fewer side effects. These findings indicate that attIL12-T cells could be a promising approach to managing sarcomas. ^{1 2 3 4 5}

Who Is on the Research Team?

John A Livingston, MD MS

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for people aged 12 and older with advanced or metastatic soft tissue or bone sarcoma, who have tried at least one systemic therapy unless none exist for their subtype. They must be in good physical condition (ECOG status of 0 or 1), not pregnant, willing to use contraception, and have proper organ function. Exclusions include active infections like hepatitis B/C, autoimmune diseases within the past two years, untreated brain metastases, recent major surgery, HIV/AIDS, other cancer treatments ongoing or a second active malignancy.

Inclusion Criteria

Measurable disease according to RECIST 1.1

My osteosarcoma cannot be surgically removed and has come back or spread.

I am 12 years old or older.

Exclusion Criteria

Active or prior documented autoimmune disease within the past 2 years

I have not received a live vaccine in the last 28 days.

I have had a primary immunodeficiency, organ transplant, or tuberculosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive attIL12-T cell therapy in combination with cyclophosphamide to determine safety and efficacy

4 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 months

What Are the Treatments Tested in This Trial?

Interventions

• attIL2-T cells
• Cyclophosphamide

Trial Overview The trial is testing attIL2-T cell therapy combined with Cyclophosphamide in patients with soft tissue or bone sarcomas. The goal is to determine a safe dosage that can control the disease. Participants will receive T-cells designed to target tumor cells directly.

How Is the Trial Designed?

Group I: Part B: Osteosarcoma Dose Expansion Experimental Treatment 2 Interventions

Participants will receive attIL2-T cell therapy at the recommended dose that was found in Phase 1.

Group II: Part A: Dose Findings (MTD) Experimental Treatment 2 Interventions

The dose of attIL2-T cell therapy the participants will receive will depend on when the participants joined this study. The first group of participants will receive the lowest dose level of attIL2-T cell therapy.

attIL2-T cells is already approved in United States for the following indications:

Approved in United States as attIL12-T cells for:

• Advanced/Metastatic Soft Tissue Sarcoma
• Bone Sarcoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study involving three adult T cell leukemia/lymphoma (ATL) patients, expanded Tax-specific CTLs showed significant therapeutic potential in NOG mice, leading to increased infiltration of CD8-positive T cells into ATL lesions and a notable decrease in ATL cell presence in the blood, spleen, and liver.

The treatment with Tax-CTL not only prolonged survival in some ATL/NOG mice but also demonstrated varying efficacy based on the patient's disease type, marking the first report of adoptive therapy with antigen-specific CTLs resulting in antitumor effects in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2Rγnull mouse model. Masaki, A., Ishida, T., Suzuki, S., et al.[2013]

Adoptive cellular therapy, particularly using tumor-infiltrating lymphocytes (TILs), shows significant promise in treating cancers like melanoma, indicating a need for further development in clinical settings.

Genetically engineered T cells can enhance antitumor activity, but there are risks of toxicity when these cells target normal tissues, highlighting the need for careful balance in future therapies and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of adoptive cell therapy for cancer: a clinical perspective. Hawkins, RE., Gilham, DE., Debets, R., et al.[2021]

The phase 1 trial showed that NY-ESO-1-specific TCR-T cells are both safe and effective for treating advanced soft tissue sarcomas, marking a significant advancement in adoptive T cell therapy.

This study represents an important step in the clinical application of T cell therapies, potentially offering new hope for patients with this challenging type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pushing forward in sarcoma with a new TCR targeting NY-ESO-1. Al-Marayaty, R., Pollack, SM.[2023]

CAR T Cell therapy is a promising new treatment for sarcomas, which have seen stagnant survival rates, particularly in recurrent or metastatic cases, highlighting the urgent need for novel therapies.

Recent studies have identified several sarcoma-associated antigens suitable for CAR T Cell targeting, such as HER2 and GD2, showing encouraging results and suggesting that this therapy could improve outcomes for sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: From mechanisms to potential clinical applications. Thanindratarn, P., Dean, DC., Nelson, SD., et al.[2020]

The TCRα-modified T cell product showed no signs of tumorigenic or mutagenic activity in vitro, indicating that the viral vectors used for its generation are safe and do not cause genetic damage.

In mouse models, the adoptive transfer of TCRα-engineered T cells did not disrupt normal body functions and showed no acute toxicity or harmful immune reactions, suggesting a favorable safety profile for potential clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. Kalinina, A., Bruter, A., Persiyantseva, N., et al.[2022]

In a study using murine sarcomas, T lymphocytes from tumor-draining lymph nodes were successfully activated in vitro with anti-TCR monoclonal antibodies and interleukin-2, leading to an eightfold increase in cell numbers and significant reduction of established pulmonary metastases.

The activated T cells demonstrated tumor-specific therapeutic efficacy, resulting in prolonged survival for treated mice, with 30% remaining tumor-free for over 90 days, indicating the potential for long-lasting systemic immunity against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy mediated by anti-TCR/IL-2-activated tumour-draining lymph node cells. Mitsuma, S., Yoshizawa, H., Ito, K., et al.[2018]

In a study involving 190 sarcoma tumor specimens, researchers successfully isolated tumor-infiltrating lymphocytes (TILs) from 54 of 92 primary sarcoma samples, indicating that certain sarcoma subtypes can provide enough TILs for potential immunotherapy.

The optimized protocol for expanding TILs demonstrated that these cells retained their ability to react and release IFNγ upon stimulation, suggesting their viability for future personalized immunotherapy treatments in sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the Potential of Isolating and Expanding Tumour-Infiltrating Lymphocytes from Adult Sarcoma. Ko, A., Coward, VS., Gokgoz, N., et al.[2022]

Liposomal avasimibe was successfully attached to T cells, enhancing their activation and antitumor efficacy without disrupting their normal functions, leading to significant improvements in treating solid tumors like melanoma and glioblastoma in mouse models.

The engineered T cells demonstrated a strong safety profile, with no significant systemic side effects observed, and showed remarkable effectiveness, completely eradicating glioblastoma in 3 out of 5 treated mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy. Hao, M., Hou, S., Li, W., et al.[2022]

Modified T-cell therapies, particularly those targeting cancer testis antigens like NY-ESO-1, show promising efficacy in treating sarcomas, with response rates of up to 60% observed in clinical trials for specific types like synovial sarcoma.

Challenges remain in the form of HLA-restriction and non-immunogenic tumor microenvironments, which may limit the effectiveness of these therapies, highlighting the need for further development to enhance T-cell specificity and persistence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of sarcomas with modified T cells. Mahalingam, P., Julve, M., Huang, P., et al.[2023]

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has shown significant promise in treating metastatic melanoma, leading to the development of genetically engineered T cells that can specifically target tumor-associated antigens (TAAs).

Initial clinical studies indicate that these genetically engineered T cells, including those with tumor antigen-specific T cell receptors (TCRs) and chimeric antigen receptors (CARs), can effectively cause tumor regression, although safety concerns, particularly regarding potential 'on-target, off-organ' toxicity, must be carefully managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. Shi, H., Liu, L., Wang, Z.[2020]

CAR-T therapy has shown significant success in treating relapsed/refractory B-cell malignancies, utilizing genetically modified T-cells to target and eliminate cancer cells effectively.

Despite its efficacy, CAR-T therapy is associated with serious toxicities such as cytokine release syndrome and neurotoxicity, necessitating improved safety measures, especially as the therapy is being tested in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building safety into CAR-T therapy. Peters, DT., Savoldo, B., Grover, NS.[2023]

Researchers developed stable T cell clones from patients with osteogenic sarcoma and malignant fibrohistiocytoma that specifically target and kill autologous tumor cells, demonstrating their potential for personalized cancer immunotherapy.

These T cell clones maintained their cytotoxic activity for over 6 months and recognized a common sarcoma-associated antigen, indicating a promising mechanism for targeting tumors while sparing normal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cellular immune response to human sarcomas: cytotoxic T cell clones reactive with autologous sarcomas. I. Development, phenotype, and specificity. Slovin, SF., Lackman, RD., Ferrone, S., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35727602/

Membrane-Anchored and Tumor-Targeted IL12 (attIL12) This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS11586

A first-in-human phase 1 trial of T cell membrane-anchored ... 2 Preclinical studies demonstrated efficacy and induction of long-term memory of ttIL12 against metastatic osteosarcoma with reduced toxicity in ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38199607/

Cell membrane-anchored and tumor-targeted IL-12 ... - PubMed Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV+ tumor cells, suppressing transforming ...

4. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05621668

NCT05621668 | A First-In-Human Phase 1 Trial of T-Cell ... Evaluate the anti-tumor efficacy achieved following adoptive transfer of T cellmembrane-anchored ... (attIL12)-T cells and correlate with clinical benefit ...

5. jitc.bmj.com jitc.bmj.com/content/12/1/e006991

Cell membrane-anchored and tumor-targeted IL-12 T ... In previous publications, we showed that attIL12-T cells can effectively inhibit large and heterogeneous osteosarcoma PDX tumors and induce T- ...