Immunomodulation Therapy + Radiation for Metastatic Breast Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Overseen byFumito Ito
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Roswell Park Cancer Institute
Must not be taking: Immunosuppressants, Chemotherapy, Immunotherapy, others
Disqualifiers: Autoimmune disease, HER2+ cancer, Mood disorders, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase I trial evaluates the safety and effectiveness of in situ immunomodulation with CDX-301, radiotherapy, CDX-1140 and Poly-ICLC (Cohort A) and these with intravenous (IV) pembrolizumab and subcutaneous (SC) tocilizumab (Cohort B) in treating patients with unresectable and measurable metastatic melanoma, cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu(-) breast cancer. CDX-301 may induce cross-presenting dendritic cells, master regulators in the immune system. Radiation therapy uses high energy to kill tumor cells and release antigens that may be picked up, processed and presented by cross-presenting dendritic cells. CDX-1140 and Poly-ICLC may activate tumor antigen-loaded,cross-presenting dendritic cells, and generate tumor-specific T lymphocytes, a type of immune cells, that can search out and attack cancers. Giving immune modulators and radiation therapy may stimulate tumor cell death and activate the immune system.
Will I have to stop taking my current medications?
The trial requires stopping certain medications. If you are currently on systemic immunosuppressive agents, you must stop them at least 3 weeks before joining the trial. Additionally, you cannot use targeted therapies or chemotherapy within 2 weeks before starting the trial, but endocrine therapy is allowed.
What data supports the effectiveness of this treatment for metastatic breast cancer?
Research on similar treatments combining radiation therapy with immune-modulating drugs, like anti-CTLA-4 and anti-PD1, has shown improved survival and enhanced immune responses in cancer models, suggesting potential benefits for this combination in treating metastatic breast cancer.
12345Is the combination of immunomodulation therapy and radiation generally safe for humans?
CDX-301 has shown promise in protecting against radiation damage in mice, indicating potential safety in humans. Poly ICLC has been used as an antiviral and antitumor agent, suggesting it may be safe. CXCR4-directed endoradiotherapy showed a favorable safety profile in patients, with manageable side effects.
16789How is the treatment of Immunomodulation Therapy + Radiation for Metastatic Breast Cancer different from other treatments?
This treatment is unique because it combines immunotherapy with radiation to enhance the body's immune response against cancer. The radiation not only targets the tumor directly but also helps the immune system recognize and attack cancer cells more effectively, potentially leading to better outcomes than using either therapy alone.
1011121314Eligibility Criteria
This trial is for adults with certain advanced cancers (melanoma, SCC, Merkel cell carcinoma, sarcomas, HER2/neu(-) breast cancer) that can't be removed by surgery. Participants must have measurable disease and agree to receive injections of CDX-301, CDX-1140, poly-ICLC and radiation therapy. They should not have had recent heart issues or other invasive cancers in the last 3 years and must not be pregnant.Inclusion Criteria
I am willing to have a biopsy of my lesion.
I need radiation therapy for symptom relief or to control the cancer, as advised by my oncologist.
My tumor is in the breast, skin, or lymph nodes, measures 2-7 cm, and can be safely injected.
+13 more
Exclusion Criteria
Patients with uncontrolled diseases other than cancer may be excluded if after consultation with PI and research team it is decided it might affect the treatment efficacy or toxicity
I'm sorry, it seems like the sentence got cut off. It looks like the criterion is incomplete. Can you please provide the full criterion so that I can help you rewrite it in plain language?
My cancer was caused by previous radiation therapy.
+26 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Patients receive recombinant Flt3 ligand intratumorally on days 1-5, undergo radiation therapy on day 8 or 9, and receive CDX-1140 and Poly-ICLC intratumorally on day 9 or 10. Treatment repeats every 21 days for 4 cycles.
12 weeks
Multiple visits per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3-6 months for 2 years.
2 years
Follow-up visits every 3-6 months
Participant Groups
The trial tests a combination of radio-immunotherapy treatments including CDX-301 to boost immune cells called dendritic cells; radiation therapy to kill tumor cells; CDX-1140 and Poly-ICLC to activate the immune system against cancer. It aims to see how well these work together in treating patients with unresectable metastatic solid tumors.
2Treatment groups
Experimental Treatment
Group I: Cohort B (immunomodulators, radiation therapy)Experimental Treatment6 Interventions
Patients receive recombinant Flt3 ligand IT on days 1-5 and also receive pembrolizumab (IV), tocilizumab (SC) as well as undergo radiation therapy on day 8 or 9. Patients also receive agonistic anti-CD40 monoclonal antibody IT and IV over 90 minutes and Poly-ICLC IT on day 9 or 10. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
Group II: Cohort A (immunomodulators, radiation therapy)Experimental Treatment4 Interventions
Patients receive recombinant Flt3 ligand IT on days 1-5 and undergo radiation therapy on day 8 or 9. Patients also receive agonistic anti-CD40 monoclonal antibody CDX-1140 IT and Poly-ICLC IT on day 9 or 10. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Los Angeles General Medical CenterLos Angeles, CA
Roswell Park Cancer InstituteBuffalo, NY
USC/Norris Comprehensive Cancer CenterLos Angeles, CA
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Who Is Running the Clinical Trial?
Roswell Park Cancer InstituteLead Sponsor
University of Southern CaliforniaLead Sponsor
National Institutes of Health (NIH)Collaborator
References
NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1 resistant lung cancer model. [2022]The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response's activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.
Pulsed radiotherapy to mitigate high tumor burden and generate immune memory. [2022]Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used with immune-check-point inhibitors in metastatic disease, especially when immunotherapy fails due to tumor immune evasion. We hypothesized that using high-dose stereotactic radiation in cycles (pulses) would increase T-cell priming and repertoire with each pulse and build immune memory in an incremental manner. To prove this hypothesis, we studied the combination of anti-CTLA-4 and Pulsed radiation therapy in our 344SQ non-small cell lung adenocarcinoma murine model. Primary and secondary tumors were bilaterally implanted in 129Sv/Ev mice. In the Pulsed XRT group, both primary and secondary tumors received 12Gyx2 radiation one week apart, and blood was collected seven days afterwards for TCR repertoire analysis. As for the delayed-Pulse group, primary tumors received 12Gyx2, and after a window of two weeks, the secondary tumors received 12Gyx2. Blood was collected seven days after the second cycle of radiation. The immunotherapy backbone for both groups was anti-CTLA-4 antibody to help with priming. Treatment with Pulsed XRT + anti-CTLA-4 led to significantly improved survival and resulted in a delayed tumor growth, where we observed enhanced antitumor efficacy at primary tumor sites beyond XRT + anti-CTLA-4 treatment group. More importantly, Pulsed XRT treatment led to increased CD4+ effector memory compared to single-cycle XRT. Pulsed XRT demonstrated superior efficacy to XRT in driving antitumor effects that were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. These results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and sustained antitumor response.
Novel antigens for targeted radioimmunotherapy in hepatocellular carcinoma. [2023]Liver cancer is the sixth common cancer and forth cause of cancer-related death worldwide. Based on usually advanced stages of hepatocellular carcinoma (HCC) at the time of diagnosis, therapeutic options are limited and, in many cases, not effective, and typically result in the tumor recurrence with a poor prognosis. Radioimmunotherapy (RIT) offers a selective internal radiation therapy approach using beta or alpha emitting radionuclides conjugated with tumor-specific monoclonal antibodies (mAbs), or specific selective peptides. When compared to chemotherapy or radiotherapy, radiolabeled mAbs against cancer-associated antigens could provide a high therapeutic and exclusive radiation dose for cancerous cells while decreasing the exposure-induced side effects to healthy tissues. The recent advances in cancer immunotherapy, such as blockade of immune-checkpoint inhibitors (ICIs), has changed the landscape of cancer therapy, and the efficacy of different classes of immunotherapy has been tested in many clinical trials. Taking into account the use of ICIs in the liver tumor microenvironment, combined therapies with different approaches may enhance the outcome in the future clinical studies. With the development of novel immunotherapy treatment options in the recent years, there has been a great deal of information about combining the diverse treatment modalities to boost the effectiveness of immunomodulatory drugs. In this opinion review, we will discuss the recent advancements in RIT. The current status of immunotherapy and internal radiotherapy will be updated, and we will propose novel approaches for the combination of both techniques. Potential target antigens for radioimmunotherapy in Hepatocellular carcinoma (HCC). HCC radioimmunotherapy target antigens are the most specific and commonly accessible antigens on the surface of HCC cells. CTLA-4 ligand and receptor, TAMs, PD-1/PD-L, TIM-3, specific IEXs/TEXs, ROBO1, and cluster of differentiation antigens CD105, CD147 could all be used in HCC radioimmunotherapy. Abbreviations: TAMs, tumor-associated macrophages; CTLA-4, cytotoxic T-lymphocyte associated antigen-4; PD-1, Programmed cell death protein 1; PD-L, programmed death-ligand1; TIM-3, T-cell immunoglobulin (Ig) and mucin-domain containing protein-3; IEXs, immune cell-derived exosomes; TEXs, tumor-derived exosomes.
Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer. [2022]The therapeutic effect of agonistic anti-OX40 (CD134) monoclonal antibody (mAb) in combination with radiotherapy was evaluated in a murine lung cancer model. After intradermal transplantation of ovalbumin (OVA)-transfected Lewis lung carcinoma, C57BL/6 mice were irradiated locally with a single dose of 20 Gy in combination with an intratumoral injection of anti-OX40 mAb at 50 microg on day 4 after transplantation, which is when the major axis of the inoculated tumor reached a diameter of 7-9 mm. On days 8, 11, and 14, the tumor-bearing mice were further treated with the same dose of anti-OX40 mAb. Anti-OX40 mAb in combination with radiotherapy prolonged survival and provided greater efficacy than either single treatment against well-established tumors. An in vivo depletion study suggested that therapeutic immunity was mainly CD8(+) T-cell dependent. OX40(+)CD8(+) T cells were augmented in draining lymph nodes obtained from irradiated mice compared with those from non-irradiated mice. OVA-major histocompatibility complex tetramer(+) CD8(+) T cells had been strongly recruited to the draining lymph nodes obtained from mice treated with anti-OX40 mAb in combination with radiotherapy, and strong antigen-specific cytotoxicity was confirmed by a (51)Cr-release assay. Moreover, a tumor-rechallenge model indicated that this combination therapy induced durable tumor immunity. Thus, anti-OX40 mAb in combination with radiotherapy may potentially help the management of patients with lung cancer.
A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model. [2022]Combining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer.
CDX-301: a novel medical countermeasure for hematopoietic acute radiation syndrome in mice. [2021]Bone marrow failure and hematopoietic damage is one of the major consequences of irradiation-induced lethality. There is an immediate need to develop medical countermeasures (MCMs) to combat irradiation-induced lethality. We tested the efficacy of CDX-301, developed by Celldex Therapeutics Inc., in mice exposed to Co-60 gamma total body irradiation (TBI). The drug demonstrated its efficacy both as a prophylactic countermeasure and a mitigator in CD2F1 mice exposed to TBI. A single dose of CDX-301 administered 24 h prior to 24 h post-exposure conferred significant survival. Accelerated recovery from irradiation-induced peripheral blood cytopenia, bone marrow damage as well as apoptosis in sternum was observed in mice pre-treated with CDX-301. Analysis of splenocytes revealed alterations in T cell profiles that were dependent on the time of drug administration. Prophylactic treatment of CDX-301 resulted in increased splenic CD3+ T cells, specifically CD4+T helper cells, compared to splenocytes from non-irradiated mice. These results indicate that CDX-301 is a promising radiation countermeasure and demonstrate its capability to protect cells within hematopoietic organs. These data support potential use of CDX-301, both pre- and post-radiation, against hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.
Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy. [2021]Purpose: There is an important need to improve the effectiveness of radio-chemotherapy (RTCT) for cervical cancer. The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases. The objective of this study was to explore the efficacy and toxicity of combining RTCT with CXCL12/CXCR4 inhibition in cervical cancer.Experimental Design: CXCR4 expression was measured in 115 patients with cervical cancer. Two primary orthotopic cervical cancer xenografts (OCICx) with different levels of CXCR4 expression were treated with RT (30 Gy: 15 daily fractions) and weekly cisplatin (4 mg/kg), with or without the CXCR4 inhibitor Plerixafor (5 mg/kg/day). The endpoints were tumor growth delay and lymph node metastases. Acute intestinal toxicity was assessed using a crypt cell assay.Results: There was a fivefold variation in CXCR4 mRNA expression in the patient samples, and good correlation between the expression in patients and in the xenografts. The combination of RTCT and Plerixafor produced substantial tumor growth delay and reduced lymph node metastases compared with RTCT alone in both of the xenograft models. There was a trend toward reduced acute intestinal toxicity with the addition of Plerixafor to RTCT. There were no changes in normal organ morphology to suggest increased late toxicity.Conclusions: This study demonstrates that the addition of Plerixafor to standard RTCT improves primary tumor response and reduces metastases in cervical cancer with no increase in toxicity. This combination warrants further investigation in phase I/II clinical trials. Clin Cancer Res; 23(5); 1242-9. ©2016 AACR.
Side Effects of CXC-Chemokine Receptor 4-Directed Endoradiotherapy with Pentixather Before Hematopoietic Stem Cell Transplantation. [2020]The chemokine receptor CXC-chemokine receptor 4 (CXCR4) is a transmembrane receptor involved in survival, proliferation, and dissemination of different cancers, including hematopoietic malignancies. Relapsed or refractory hematopoietic cancers are frequently resistant to conventional therapy, and novel highly active strategies are urgently needed. CXCR4-directed endoradiotherapy constitutes a highly promising targeted therapeutic concept. Here, we investigated the adverse effects of this novel treatment approach. Methods: Twenty-two patients with heavily pretreated lymphoproliferative or myeloid malignancies were treated with 177Lu- or 90Y-pentixather-a CXCR4-directed therapeutic radioligand-before conventional conditioning therapy followed by autologous or allogeneic hematopoietic stem cell transplantation. Twenty-five CXCR4-directed endoradiotherapies were administered to those patients. Adverse events occurring between endoradiotherapy and the start of conventional conditioning therapy were retrospectively analyzed and graded for the estimation of the safety profile. Results: CXCR4-directed endoradiotherapy with pentixather showed a favorable toxicity profile. As expected, the hematopoietic system was most affected, with all subjects developing cytopenias. Except for 1 acute kidney failure, grade 3, due to tumor lysis syndrome, overall nephro- and hepatotoxicity was low. Other higher-grade adverse events were either transient and resolved or easily manageable. Conclusion: Therapy with radiolabeled pentixather appears to be well tolerated and easily applicable when preceding conventional conditioning regimens for hematopoietic stem cell transplantation.
Poly ICLC induces anti-IC antibodies in mice and rabbits. [2020]Poly ICLC is an interferon (IFN) inducer and antiviral, antitumor, radioprotective, and immunoregulatory agent. We show that administration of poly ICLC to mice and rabbits also results in the presence of anti-IC antibodies in their serum.
The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches. [2021]Advances in the immunological pharmaceuticals, such as checkpoint inhibitors and agonists, have positive implications for the future of the radiotherapy abscopal response. A once rare phenomenon, whereby distant nonirradiated tumor sites regressed after radiotherapy alone, may become more common when combined with the immune modulating agents. Radiotherapy can increase neoantigen expression, increased tumor PD-L1 expression, increase MHC class I expression, reverse exhausted CD8 T cells and increase tumor-infiltrating tumors within the tumor microenvironment. These changes in the tumor and the tumor microenvironment after radiotherapy could potentiate responses to anti-CTL-4, anti-PD-L1/PD-1 and other immunotherapy agents. Thus, advances in checkpoint inhibitors have increased interest in re-evaluation of the role of conventional radiotherapy approaches on the immune system. We reviewed newer nonconventional approaches such as SBRT-PATHY, GRID, FLASH, carbon ion and proton therapy and their role in eliciting immune responses. We believe that combining these novel radiation methods may enhance the outcome with the newly US FDA approved immune modulating agents.
The optimism surrounding stereotactic body radiation therapy and immunomodulation. [2018]In recent years, rapidly evolving radiation techniques have enabled the precise delivery of very high doses of radiation to local targets with stereotactic ablative body radiotherapy (SABR). In addition to its direct cytotoxicity, radiation and in particular SABR has powerful immunomodulatory effects resulting in immunogenic cell death and potentiation of the anti-tumour immune response. However, due to the immunosuppressive nature of non-irradiated sites of metastases, radiotherapy alone is seldom sufficient to induce the systemic response required for distant tumour rejection. Immune checkpoint inhibitors are a novel class of immunomodulatory agents shown to have robust efficacy against a number of malignancies. These drugs can augment the effects of radiotherapy by helping overcome tumour-induced immunosuppression at local and distant sites. Similarly, radiation may complement immunotherapy by priming tumours in preparation for the adaptive immune response, thereby leading to more prolonged clinical effects. This synergistic relationship has been demonstrated in laboratory models and has been extended to a number of early phase clinical studies.
Trial Watch: Anticancer radioimmunotherapy. [2021]Radiotherapy has extensively been employed as a curative or palliative intervention against cancer throughout the last century, with a varying degree of success. For a long time, the antineoplastic activity of X- and γ-rays was entirely ascribed to their capacity of damaging macromolecules, in particular DNA, and hence triggering the (apoptotic) demise of malignant cells. However, accumulating evidence indicates that (at least part of) the clinical potential of radiotherapy stems from cancer cell-extrinsic mechanisms, including the normalization of tumor vasculature as well as short- and long-range bystander effects. Local bystander effects involve either the direct transmission of lethal signals between cells connected by gap junctions or the production of diffusible cytotoxic mediators, including reactive oxygen species, nitric oxide and cytokines. Conversely, long-range bystander effects, also known as out-of-field or abscopal effects, presumably reflect the elicitation of tumor-specific adaptive immune responses. Ionizing rays have indeed been shown to promote the immunogenic demise of malignant cells, a process that relies on the spatiotemporally defined emanation of specific damage-associated molecular patterns (DAMPs). Thus, irradiation reportedly improves the clinical efficacy of other treatment modalities such as surgery (both in neo-adjuvant and adjuvant settings) or chemotherapy. Moreover, at least under some circumstances, radiotherapy may potentiate anticancer immune responses as elicited by various immunotherapeutic agents, including (but presumably not limited to) immunomodulatory monoclonal antibodies, cancer-specific vaccines, dendritic cell-based interventions and Toll-like receptor agonists. Here, we review the rationale of using radiotherapy, alone or combined with immunomodulatory agents, as a means to elicit or boost anticancer immune responses, and present recent clinical trials investigating the therapeutic potential of this approach in cancer patients.
A perspective on the impact of radiation therapy on the immune rheostat. [2018]The advent and success of immune checkpoint inhibitors (ICIs) in cancer treatment has broadened the spectrum of tumours that might be considered "immunogenic" and susceptible to immunotherapeutic (IT) intervention. Not all cancer types are sensitive, and not all patients with any given type respond. Combination treatment of ICIs with an established cytotoxic modality such as radiation therapy (RT) is a logical step towards improvement. For one, RT alone has been shown to be genuinely immunomodulatory and secondly pre-clinical data generally support combined ICI-RT approaches. This new integrated therapy for cancer treatment holds much promise, although there is still a lot to be learned about how best to schedule the treatments, manage the toxicities and determine what biomarkers might predict response, as well as many other issues. This review examines how RT alters the immune rheostat and how it might best be positioned to fully exploit IT.
Immunotherapy and radiation. [2014]Radiation therapy and immunotherapy are both well-established treatments for malignant disease. Radiotherapy has long been utilized for purposes of providing local tumor control, and the recent success with novel immunomodulatory agents has brought immunotherapy into the forefront of clinical practice for the treatment of many tumor types. Although radiotherapy has traditionally been thought to mediate tumor regression through direct cytotoxic effects, it is now known that radiation also alters the local tumor microenvironment with effects on both the local and systemic anti-tumor immune response. There is growing evidence that the rational integration of the immunomodulatory effects of radiotherapy with the expanding armamentarium of clinically approved immunotherapeutics can yield potent anti-tumor responses exceeding the benefit of either therapy alone. Here we summarize current approaches to the combination of immunotherapy with radiation therapy.