Immunotherapy + Radiation for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Auto-immune disease, Brain metastases, Hepatitis, others

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

Compensation: Varies

Number of Visits: 7

Duration: 1 week

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of M5A-IL2 immunocytokine (M5A-ICK) combined with stereotactic body radiation therapy (SBRT) and to see how well they work in treating patients with colorectal cancer or xarcinoembryonic antigen (CEA) positive breast cancer that cannot be removed by surgery (unresectable) or has spread from where it first started (primary site) to other places in the body (metastatic). Carcinoembryonic Antigen (CEA) is a protein that is present in most colorectal cancers and in many other cancers, such as breast cancer, as well. SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Cytokines are signaling proteins that help control inflammation in the body. They allow the immune system to mount a defense if germs or cancer or other substances that can make people sick enter the body. Interleukin-2 (IL-2) is a powerful cytokine able to regulate the immune responses that are important for anticancer immunity. Immunocytokines (also called antibody-cytokine fusion proteins) are small proteins that regulate the activity of immune cells. The M5A-IL2 immunocytokine (M5A-ICK) combines the cancer targeting features of the M5A antibody with the immune system regulation properties of the cytokine IL-2. Giving M5A-ICK in combination with standard of care (SOC) SBRT may work better in treating patients with unresectable metastatic colorectal cancer or CEA positive metastatic breast cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be at least 4 weeks from your last cytotoxic or biological agent, except for mitomycin C, which requires a 6-week break, and prior immunotherapy, which requires a 3-month break before starting the trial.

What data supports the effectiveness of the treatment Immunotherapy + Radiation for Cancer?

Research shows that combining immunocytokines like M5A-IL2 with radiation can enhance the immune response against tumors, leading to significant tumor reduction and improved survival in animal models. This combination therapy can also trigger a strong anti-tumor immune response and reduce the growth of tumors, suggesting potential effectiveness in cancer treatment. ^{1 2 3 4 5}

Is the combination of immunotherapy and radiation generally safe for humans?

The safety of combining immunotherapy with radiation has been evaluated in several studies. For example, a phase 1 study found that L19-IL2 combined with stereotactic body radiation therapy (SBRT) was safe and tolerable. Additionally, a phase Ib trial in patients with metastatic non-small cell lung carcinoma showed that NHS-IL2 combined with radiotherapy was safe and tolerable after chemotherapy. ^{1 4 5 6 7}

What makes the M5A-IL2 immunocytokine treatment unique for cancer?

The M5A-IL2 immunocytokine treatment is unique because it combines a tumor-specific antibody with interleukin-2 (IL-2), enhancing the immune system's ability to target and destroy cancer cells while reducing the toxic side effects typically associated with high doses of IL-2. This treatment, when combined with radiation, can lead to significant tumor reduction and potentially complete regression by activating immune cells directly within the tumor environment. ^{1 2 3 4 5}

Research Team

Jeffrey Wong

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with metastatic colorectal or CEA positive breast cancer that's not operable. Participants must have stable health, an expected survival of at least 3 months, and meet specific blood count and organ function criteria. They should be past certain waiting periods after previous treatments and agree to use effective contraception if applicable.

Inclusion Criteria

Your liver enzymes (AST/ALT) should be within a certain range.

Your platelet count is higher than 100,000 per cubic millimeter.

Your bilirubin levels are within the normal range.

Exclusion Criteria

My electrolyte levels cannot be corrected to a mild condition.

I have active cancer spread to my brain.

I am of child-bearing age and do not use birth control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Radiation

Participants undergo standard of care SBRT over 3 fractions on days 1, 3, and 5

1 week

3 visits (in-person)

Treatment

Participants receive M5A-IL2 immunocytokine subcutaneously on days 8, 9, and 10

1 week

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Multiple visits (in-person and virtual)

Treatment Details

Interventions

• M5A-IL2 immunocytokine (M5A-ICK)
• Stereotactic Body Radiation Therapy

Trial Overview The trial tests M5A-IL2 immunocytokine combined with stereotactic body radiation therapy (SBRT) to treat unresectable metastatic cancers. It aims to find the safest dose and see how well it works by targeting cancer cells while activating the immune system.

Participant Groups

Group I: Treatment (SBRT, M5A-IL2 ICK) Experimental Treatment 8 Interventions

Patients undergo SOC SBRT over 3 fractions on days 1, 3, and 5, followed by M5A-ICK SC on days 8, 9, and 10 once daily for a single cycle on study. Patients undergo CT or PET/CT as well as blood sample collection throughout the trial. Patients may undergo magnetic resonance imaging or bone scan as clinically indicated on the trial. Additionally, patients may optionally undergo tissue biopsy during screening and on study.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 1 clinical trial involving 6 patients with oligometastatic solid tumors, the immunocytokine L19-IL2 was found to be well tolerated at a dose of 15 million International Units (Mio IU) after stereotactic body radiation therapy (SBRT), with no dose-limiting toxicity reported.

The study identified 2 long-term progression-free responders, suggesting potential therapeutic efficacy, and established that the recommended phase 2 dose for future trials combining SBRT with L19-IL2 is 15 Mio IU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study. Van Limbergen, EJ., Hoeben, A., Lieverse, RIY., et al.[2021]

IL-2 immunocytokines effectively target the tumor microenvironment, promoting the activation of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes, which helps shift the immune response towards a more effective anti-tumor response.

These immunocytokines can achieve potent anti-cancer effects while minimizing severe toxicities associated with high-dose systemic IL-2, as shown in preclinical models and early clinical trials, and they show promise when combined with other cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy. Mortara, L., Balza, E., Bruno, A., et al.[2020]

Combining local radiotherapy with intratumoral injections of tumor-specific antibodies, particularly an IL2-linked immunocytokine, significantly enhances antitumor immune responses, leading to complete tumor regression in most tested mice with melanoma, neuroblastoma, and head and neck squamous cell carcinoma.

The addition of immune checkpoint blockade to this combination therapy further improves tumor response and survival in mice with large tumors or metastases, suggesting a promising strategy for enhancing cancer treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. Morris, ZS., Guy, EI., Francis, DM., et al.[2018]

Irradiation of rhabdomyosarcoma (A204) xenografts significantly increased the accumulation of the immunocytokine NHS-IL12, suggesting that combining radiation therapy with NHS-IL12 could enhance its anti-tumor effects.

In contrast, prostate cancer (PC3) xenografts did not show increased NHS-IL12 uptake after irradiation, indicating that the effectiveness of this treatment may depend on the specific type of tumor being targeted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models. Eckert, F., Schmitt, J., Zips, D., et al.[2021]

The antibody-IL-2 fusion protein (ICK) targeting CEA-positive tumors showed significant tumor eradication in a transgenic mouse model, indicating its potential as an effective cancer treatment.

ICK therapy reduced the presence of regulatory T cells (Tregs) in tumors compared to anti-CEA antibody treatment, suggesting it may enhance anti-tumor immunity without increasing Treg activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation. Kujawski, M., Sherman, M., Hui, S., et al.[2021]

In a study involving 61 melanoma and neuroblastoma patients, 52% developed an anti-idiotypic antibody response to the immunocytokine hu14.18-IL2, which may interfere with the detection of the treatment in the bloodstream.

The development of these antibodies did not correlate with any clinical toxicity, suggesting that while the immune response occurs, it does not negatively impact patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. Hank, JA., Gan, J., Ryu, H., et al.[2023]

In preclinical studies, the combination of NHS-IL2 and radiotherapy led to significant tumor regression in 80%-100% of treated mice, indicating strong antitumor activity.

In a phase Ib trial with 13 patients suffering from metastatic non-small cell lung carcinoma, NHS-IL2 was well tolerated, with no maximum tolerated dose reached, and two patients experienced long-term survival, suggesting potential clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy. van den Heuvel, MM., Verheij, M., Boshuizen, R., et al.[2021]

References

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

Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy. [2020]

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

In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. [2018]

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

Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models. [2021]

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

Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation. [2021]

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

Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy. [2021]