Immunotherapy + Radiation for Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: Auto-immune disease, Brain metastases, Hepatitis, others
No Placebo Group
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.
12345Is 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.
14567What 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.
12345Eligibility 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.
+22 more
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.
+13 more
Trial 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)
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (SBRT, M5A-IL2 ICK)Experimental Treatment8 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study. [2021]The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed.
Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy. [2020]Antibody-cytokine fusion proteins (immunocytokine) exert a potent anti-cancer effect; indeed, they target the immunosuppressive tumor microenvironment (TME) due to a specific anti-tumor antibody linked to immune activating cytokines. Once bound to the target tumor, the interleukin-2 (IL-2) immunocytokines composed of either full antibody or single chain Fv conjugated to IL-2 can promote the in situ recruitment and activation of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes (CTL). This recruitment induces a TME switch toward a classical T helper 1 (Th1) anti-tumor immune response, supported by the cross-talk between NK and dendritic cells (DC). Furthermore, some IL-2 immunocytokines have been largely shown to trigger tumor cell killing by antibody dependent cellular cytotoxicity (ADCC), through Fcγ receptors engagement. The modulation of the TME can be also achieved with immunocytokines conjugated with a mutated form of IL-2 that impairs regulatory T (Treg) cell proliferation and activity. Preclinical animal models and more recently phase I/II clinical trials have shown that IL-2 immunocytokines can avoid the severe toxicities of the systemic administration of high doses of soluble IL-2 maintaining the potent anti-tumor effect of this cytokine. Also, very promising results have been reported using IL-2 immunocytokines delivered in combination with other immunocytokines, chemo-, radio-, anti-angiogenic therapies, and blockade of immune checkpoints. Here, we summarize and discuss the most relevant reported studies with a focus on: (a) the effects of IL-2 immunocytokines on innate and adaptive anti-tumor immune cell responses as well as immunosuppressive Treg cells and (b) the approaches to circumvent IL-2-mediated severe toxic side effects.
In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments. [2018]Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929-41. ©2016 AACR.
Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models. [2021]NHS-IL12 is an immunocytokine targeting necrotic tumour areas. IL12 shows anti-tumour activity. As local irradiation might induce additional necrosis in solid tumours, we aimed to evaluate the increase in intratumoural accumulation of NHS-IL12 after irradiation and correlate the findings with diffusion-weighted MRI studies in two xenograft models.
Potent immunomodulatory effects of an anti-CEA-IL-2 immunocytokine on tumor therapy and effects of stereotactic radiation. [2021]While anti-CEA antibodies have no direct effect on CEA-positive tumors, they can be used to direct potent anti-tumor effects as an antibody-IL-2 fusion protein (immunocytokine, ICK), and at the same time reduce the toxicity of IL-2 as a single agent. Using a fusion protein of humanized anti-CEA with human IL-2 (M5A-IL-2) in a transgenic murine model expressing human CEA, we show high tumor uptake of the ICK to CEA-positive tumors with additional lymph node targeting. ICK treated CEA-positive tumors exhibit significant tumor eradication. Analysis of tumor-infiltrating lymphocytes shows a high frequency of both CD8+ and CD4+ T cells along with CD11b positive myeloid cells in ICK treated mice. The frequency of tumor-infiltrating FoxP3+ CD4+ T cells (Tregs) is significantly reduced vs anti-CEA antibody-treated controls, indicating that ICK did not preferentially stimulate migration or proliferation of Tregs to the tumor. Combination therapy with anti-PD-1 antibody did not improve tumor reduction over ICK therapy alone. Since stereotactic tumor irradiation (SRT), commonly used in cancer therapy has immunomodulatory effects, we tested combination SRT+ICK therapy in two tumor model systems. Use of fractionated vs single high dose SRT in combination with ICK resulted in greater tumor inhibition and immunity to tumor rechallenge. In particular, tumor microenvironment and myeloid cell composition appear to play a significant role in the response rate to ICK+SRT combination therapy.
Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. [2023]Immunocytokine (IC) hu14.18-IL2 is a fusion protein of humanized antidisialoganglioside (GD2) antibody (hu14.18) and interleukin (IL)-2. Sixty-one melanoma and neuroblastoma patients received IC in phase I/Ib studies. Patient sera were examined in ELISA to determine if an anti-IC antibody response occurred during treatment.
NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy. [2021]NHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy.