Cell Therapy for Relapsed/Refractory Head and Neck Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: UNC Lineberger Comprehensive Cancer Center
Disqualifiers: Heart disease, Stroke, Hypersensitivity, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
The purpose of this study is to test the safety and tolerability of using a new treatment called autologous T lymphocyte chimeric antigen receptor cells against the CSPG4 antigen (iC9.CAR-CSPG4 T cells) in patients with head and neck cancer that came back after receiving standard therapy for this cancer. The iC9.CAR-CSPG4 treatment is experimental and has not been approved by the Food and Drug Administration. How many (dose) of the iC9.CAR. CSPG4 T cells are safe to use in patients without causing too many side effects, and what is the maximum dose that could be tolerated will be investigated. The information collected from the study would help cancer patients in the future. There are two parts to this study. In part 1, blood will be collected to prepare the iC9.CAR-CSPG4 T cells. Disease fighting T cells will be isolated and modified to prepare the iC9.CAR-CSPG4 T cells. In part 2, the iC9.CAR-CSPG4 T cells are given by infusion after completion of lymphodepletion chemotherapy. The data from the dose escalation will be used to determine a recommended phase 2 dose (RP2D), which will be decided based on the maximum tolerated dose (MTD). Additionally, recommended phase 2 dose will be tested. Eligible subjects will receive lymphodepletion chemotherapy standard followed by infusion of iC9-CAR.CSPG4 T cells. After treatment completion or discontinuation, subjects will be followed since involving gene transfer experiments.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, since the trial involves chemotherapy and cell infusion, it's best to discuss your current medications with the trial team.
What data supports the effectiveness of the treatment iC9.CAR-CSPG4 T cells for relapsed/refractory head and neck cancer?
The research on similar treatments, like CAR-T cells targeting other proteins in head and neck cancer, shows promising results in reducing tumor size and inhibiting growth. Additionally, the use of engineered immune cells, such as NK cells, has demonstrated effectiveness in killing cancer cells in head and neck cancer, suggesting potential for CAR-T cell therapies targeting CSPG4.12345
Is CAR-T cell therapy safe for humans?
CAR-T cell therapy, including treatments like iC9.CAR-CSPG4 T cells, has shown promise in treating certain cancers, but it can cause serious side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While medical management for these side effects has improved, there is still a risk of unpredictable toxicities, especially when used for solid tumors.678910
What makes the iC9.CAR-CSPG4 T cell treatment unique for head and neck cancer?
The iC9.CAR-CSPG4 T cell treatment is unique because it uses genetically engineered T cells to specifically target CSPG4, a protein often found on cancer cells, offering a personalized approach that differs from standard chemotherapy or radiation. This treatment represents a novel form of immunotherapy, potentially providing an option for patients with relapsed or refractory head and neck cancer who have limited treatment choices.2451112
Research Team
Jared Weiss, MD
Principal Investigator
UNC Lineberger Comprehensive Cancer Center
Eligibility Criteria
This trial is for adults over 18 with recurrent/metastatic squamous cell carcinoma of the head and neck, who have a Karnofsky score above 60%, indicating they can care for themselves. It's not open to those with severe heart disease, recent stroke or TIA, or allergies to cyclophosphamide or fludarabine.Inclusion Criteria
I am mostly able to care for myself.
The subject has been provided with, and given written consent for, disclosure of their personal health information along with a HIPAA authorization form which was adequately explained to them and signed.
My cancer is a type of squamous cell carcinoma in the head or neck area.
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Exclusion Criteria
I do not have severe heart problems like uncontrolled high blood pressure or recent heart attacks.
I have not had a stroke or TIA in the last year.
You have had a strong allergic reaction in the past to cyclophosphamide or fludarabine.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Cell Preparation
Blood is collected to prepare the iC9.CAR-CSPG4 T cells. Disease-fighting T cells are isolated and modified.
4 weeks
Lymphodepletion Chemotherapy
Participants receive lymphodepletion chemotherapy prior to T cell infusion.
1 week
Treatment
iC9.CAR-CSPG4 T cells are given by infusion after completion of lymphodepletion chemotherapy.
4 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of toxicity and response rates.
Up to 2 years
Treatment Details
Interventions
- iC9.CAR-CSPG4 T cells (CAR T-cell Therapy)
Trial OverviewThe study tests autologous CAR-T cells targeting CSPG4 in patients whose head and neck cancer returned after standard treatment. The safety and tolerable dose levels are being determined. Patients will undergo lymphodepletion chemotherapy before receiving the experimental iC9.CAR-CSPG4 T cell infusion.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Chimeric Antigen ReceptorsExperimental Treatment3 Interventions
blood will be collected to prepare the iC9.CAR-CSPG4 T cells. Disease-fighting T cells will be isolated and modified to prepare the iC9.CAR-CSPG4 T cells. In part 2, the iC9.CAR-CSPG4 T cells are given by infusion after completion of lymphodepletion chemotherapy.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Lineberger Comprehensive Cancer Center at University of North Carolina Chapel HillChapel Hill, NC
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Who Is Running the Clinical Trial?
UNC Lineberger Comprehensive Cancer Center
Lead Sponsor
Trials
377
Patients Recruited
95,900+
Bellicum Pharmaceuticals
Industry Sponsor
Trials
28
Patients Recruited
1,400+
University Cancer Research Fund at Lineberger Comprehensive Cancer Center
Collaborator
Trials
5
Patients Recruited
150+
National Cancer Institute (NCI)
Collaborator
Trials
14080
Patients Recruited
41,180,000+
References
Direct and antibody-dependent cell-mediated cytotoxicity of head and neck squamous cell carcinoma cells by high-affinity natural killer cells. [2021]High affinity natural killer cells (haNKs) are a cell therapy product capable of mediating both direct and antibody-dependent cell-mediated cytotoxicity (ADCC). These cells may be particularly useful in tumors that escape T-cell anti-tumor immunity by harboring antigen processing and presentation defects. Here, we demonstrated that haNKs directly kill both HPV-positive and negative head and neck squamous cell carcinoma cells. Variable tumor cell sensitivity to haNK direct cytotoxicity did not correlated with MHC class I chain-related protein A or B (MICA or MICB) expression. Importantly, haNK killing was significantly enhanced via ADCC mediated by cetuximab or avelumab in cells with higher baseline EGFR or PD-L1 expression, respectively. The ability of IFNγ to induce tumor cell PD-L1 expression correlated with enhanced PD-L1-specific ADCC. IFNγ induced neither tumor cell EGFR expression nor EGFR-specific ADCC. Although a single dose of 8 Gy IR did not appear to directly enhance susceptibility to haNK killing alone, enhanced PD-L1- and EGFR-mediated ADCC after IR correlated with increased PD-L1 and EGFR expression in one of four models. This pre-clinical evidence supports the investigation of haNK cellular therapy in combination with ADCC-mediating mAbs, with or without IR, in the clinical trial setting for patients with advanced HNSCCs. Given the MHC-unrestricted nature of this treatment, it may represent an opportunity to treat patients with non-T-cell inflamed tumors.
Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study. [2023]Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.
Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells. [2021]Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.
Immunotherapy Approaches Beyond PD-1 Inhibition: the Future of Cellular Therapy for Head and Neck Squamous Cell Carcinoma. [2023]In a span of a few years, the surprising early successes of programmed cell death 1 (PD-1) inhibitors across a vast range of tumor types have transformed our understanding of cancer immunogenicity and provided proof of principle that T cells, if manipulated, can mediate meaningful tumor regression. In head and neck cancer, only a minority of patients respond to PD-1 therapy, but these small outcomes have fueled the enthusiasm for the next generation of immunotherapy-adoptive cell therapy-which employs recent advances in genetic engineering and cell culturing methods to generate T cells with enhanced anti-tumor efficacy for infusion back into the patient. Head and neck cancer is comprised of biologically distinct cancers, HPV-positive and HPV-negative, and the clinical responses to PD-1 inhibitors in both HPV-positive and HPV-negative head and neck patients have showcased better than any other cancer type that there are distinct pathways to immunogenicity that may lend themselves to different therapeutic approaches. Thus, head and neck cancer is uniquely poised to benefit from the personalized approach of adoptive cell therapy as well as provide a valuable platform to explore contrasting T cell modalities. In this article, we will review the growing portfolio of trials of adoptive cell therapies in head and neck cancer and discuss the future directions of this emerging new field.
Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC). [2021]Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled "Immune Response Evaluation to Curative conventional Therapy" (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy.
Building safety into CAR-T therapy. [2023]Chimeric antigen receptor T cell (CAR-T) therapy is an innovative immunotherapeutic approach that utilizes genetically modified T-cells to eliminate cancer cells using the specificity of a monoclonal antibody (mAb) coupled to the potent cytotoxicity of the T-lymphocyte. CAR-T therapy has yielded significant improvements in relapsed/refractory B-cell malignancies. Given these successes, CAR-T has quickly spread to other hematologic malignancies and is being increasingly explored in solid tumors. From early clinical applications to present day, CAR-T cell therapy has been accompanied by significant toxicities, namely cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target off-tumor (OTOT) effects. While medical management has improved for CRS and ICANS, the ongoing threat of refractory symptoms and unanticipated idiosyncratic toxicities highlights the need for more powerful safety measures. This is particularly poignant as CAR T-cell therapy continues to expand into the solid tumor space, where the risk of unpredictable toxicities remains high. We will review CAR-T as an immunotherapeutic approach including emergence of unique toxicities throughout development. We will discuss known and novel strategies to mitigate these toxicities; additional safety challenges in the treatment of solid tumors, and how the inducible Caspase 9 "safety switch" provides an ideal platform for continued exploration.
CAR T-cell therapy of solid tumors. [2018]The potential for immunotherapy as a treatment option for cancer is clear from remarkable responses of some leukemia patients to adoptive cell transfer using autologous T cells genetically modified to express chimeric antigen receptors (CARs). However, the vast majority of cancers, in particular the more common solid cancers, such as those of the breast, colon and lung, fail to respond significantly to infusions of CAR T cells. Solid cancers present some formidable barriers to adoptive cell transfer, including suppression of T-cell function and inhibition of T-cell localization. In this review, we discuss the current state of CAR T-cell therapy in solid cancers, the variety of concepts being investigated to overcome these barriers as well as approaches aimed at increasing the specificity and safety of adoptive cell transfer.
Current development of chimeric antigen receptor T-cell therapy. [2020]Chimeric antigen receptor (CAR) T-cell therapy has achieved great success in recent years, with encouraging complete remission rate and long-term durability of response, especially in advanced B-cell malignancies. With the approval of tisagenlecleucel and axi-cel by FDA to treat refractory/relapsed acute lymphoblastic leukemia and non-Hodgkin lymphoma, our understanding of CAR T cells has been progressing rapidly. In this review, we discussed the designs of CAR T cells, factors affecting response, adverse effects, as well as application beyond B-cell malignancies.
CAR T-cell therapy and critical care : A survival guide for medical emergency teams. [2021]Chimeric antigen receptor (CAR) T‑cells are genetically engineered to give T‑cells the ability to attack specific cancer cells, and to improve outcome of patients with refractory/relapsed aggressive B‑cell malignancies. To date, several CAR T‑cell products are approved and additional products with similar indication or extended to other malignancies are currently being evaluated. Side effects of CAR T‑cell treatment are potentially severe or even life-threatening immune-related toxicities, specifically cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Consequently, medical emergency teams (MET) are increasingly involved in the assessment and management of CAR T‑cell recipients. This article describes the principles of CAR T‑cell therapy and summarizes the main complications and subsequent therapeutic interventions aiming to provide a survival guide for METs with a proposed management algorithm.
Adoptive immunotherapy with CAR modified T cells in cancer: current landscape and future perspectives. [2022]Cellular therapies are a rapidly evolving approach to treat cancer in the light of their unique mechanism of action that potentially overcomes drug resistance and induces durable remissions. Modalities of adoptive cell therapy include gene-modified T cells expressing novel T cell receptors or chimeric antigen receptors (CAR) that modify the immune system to recognize tumor cells and carry out potent anti-tumor effector functions. CAR T cells have shown very promising clinical results and several trials are being conducted worldwide to establish their role in cancer treatment. Most successful results have been observed in lymphoproliferative disorders with the use of CD19-directed CAR T cells, which led to their commercial approval by FDA. In this review, we provide a comprehensive overview of the current role of CAR T cell therapies in hematological malignancies and solid tumors, their associated toxicities and potential future developments in the armamentarium for cancer treatment.
Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer. [2022]Despite several advances, 5-year survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unchanged at only 50%. The commonest cause of death is locally advanced/recurrent disease. Consequently, there is an unmet need for new approaches to improve local control in HNSCC. T4 immunotherapy is an autologous cell therapy in which peripheral blood T-cells are genetically engineered using a retroviral vector to coexpress two chimeric receptors: (i) T1E28z is a chimeric antigen receptor that engages multiple ErbB dimers that are commonly upregulated in HNSCC; (ii) 4αβ is a chimeric cytokine receptor that converts the weak mitogenic stimulus provided by interleukin (IL)-4 into a strong and selective growth signal, allowing preferential expansion and enrichment of T4(+) T-cells ex vivo. T4 immunotherapy exerts antitumor activity against HNSCC cell lines and tumors in vivo, without significant toxicity. Human T4(+) T-cells also engage mouse ErbB receptors, permitting safety testing in SCID Beige mice. Severe toxicity caused by cytokine release syndrome ensues when human T4(+) T-cells are administered at high doses to mice, particularly with advanced tumor burdens. However, such toxicity is not required for efficacy and is never seen if T-cells are administered by the intratumoral route. To exploit this, we have designed a first-in-man clinical trial in which T4(+) T-cells are administered to patients with locally advanced/recurrent HNSCC. Cells will be administered at a single sitting to multiple sites around the viable tumor circumference. A 3+3 dose escalation design will be used, starting at 10(7) cells (cohort 1), escalating to 10(9) cells (cohort 5). If maximum tolerated dose remains undefined, cohorts 6/7 will receive either low- or high-dose cyclophosphamide before 10(9) T4(+) T-cells. A panel of routine/in-house assays and imaging techniques will be used to monitor safety, efficacy, perturbation of endogenous antitumor immunity, immunogenicity, and T-cell trafficking.
Genomic and Immune Approach in Platinum Refractory HPV-Negative Head and Neck Squamous Cell Carcinoma Patients Treated with Immunotherapy: A Novel Combined Profile. [2022]Only a minority of patients with platinum refractory head and neck squamous cell carcinoma (PR/HNSCC) gain some lasting benefit from immunotherapy.