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Overview of Research on Immunotherapy of Head and Neck Cancer (HNC)
Overview of Research on Immunotherapy of Head and Neck Cancer (HNC). Head and neck cancer (HNC) is one of the most common cancers in the world, which includes malignant tumors of the lips, oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx.
Most head and neck cancers are head and neck squamous cell carcinomas (HNSCC), which are often caused by infection with high-risk human papillomavirus (HPV), bad lifestyle habits such as smoking and heavy drinking. The 5-year overall survival rate of traditional treatment strategies for HNSCC such as surgery, radiotherapy and chemotherapy is only 30%-65%. As a result, the HNC immunotherapy strategies developed in recent years have received extensive attention.
Recently, Some researchers published a review article in Cancer Cell Int, which elaborated on the latest research progress of the four HNC immunotherapies, as well as the current difficulties and challenges.
Immune response to head and neck cancer
Normally, the immune system can recognize cancer cells and destroy them. However, due to the heterogeneous composition of the tumor microenvironment (TME), suppressive immune cells are produced and suppressive cytokines are released, leading to immune escape of tumors.
The immunosuppressive cell population includes: regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAM).
FOXP3Tregs in HNSCC produce immunosuppressive TME by highly expressing immune checkpoint receptors, and their high invasiveness is related to the overall survival rate of cancer patients.
derived from bone marrow progenitor cells and immature myeloid cells, can express a variety of pro-angiogenic factors and matrix metalloproteinases (MMPs) after recruitment to TME, which directly promotes tumor angiogenesis. High expression of ARG1, iNOS and Ros inhibits the specific anti-tumor immunity mediated by T cells and the natural anti-tumor immunity mediated by NK cells and macrophages.
Divided into anti-tumor macrophages M1 type and tumor-promoting macrophages M2 type. Type M2 predominates in TME of HNSCC and is related to poor prognosis. The immunosuppressive mechanism mediated by it is similar to that of MDSC, including consumption of local nutrition required for T cell function, secretion of immunosuppressive cytokines, expression of PD-L1, and recruitment of Tregs.
(The picture shows the composition of immune cells in the tumor microenvironment (TME))
Immune escape mechanism
(1) Tumor soluble factors released by cancer cells have direct immunosuppressive effects, including inducing T cell apoptosis.
(2) The up-regulation of inhibitory checkpoint molecules such as PD-1 and CTLA-4 can impair the initiation of memory T cells and promote memory T cell failure under chronic stimulation.
(3) The impaired costimulatory signal prevents the effective activation of anti-tumor immunity.
(4) Recruit inhibitory cell populations to further induce the immunosuppressive state of the tumor microenvironment.
Immunotherapy strategies for head and neck cancer
A. Oncolytic virus immunotherapy
Oncolytic viruses (OVs) can specifically target and infect, lyse and kill tumor cells without affecting normal cells. Lysed tumor cells stimulate immune cells to enhance anti-tumor immune response by releasing tumor-associated antigens (TAAs), pathogen-related molecular patterns (PAMPs) and damage-related molecular patterns (DAMPs).
Adenovirus (Ads): A 36kb double-stranded DNA non-enveloped virus, the main receptors are Coxsackie virus Ad receptor (CAR), CD46, CD80, DSG2.
Oncorine (H101): Based on Ad5, the E1B-55k gene and E3 gene have been deleted to ensure its replication and safety in p53-deficient tumor cells. In 2005, China approved the combination of the virus with 5-fluorouracil (5-FU) and cisplatin to treat nasopharyngeal carcinoma.
CAdVEC: A binary structure composed of oncolytic adenovirus Ad and helper-dependent Ad (HDAd), which can insert a 34kb foreign gene. Insertion of IL-12 and PD-L1 (CAdVECIL12_PDL1) combined with HER2-specific CAR-T cells can inhibit tumor growth and prolong survival. The phase I trial of CAdVEC mixed with HER2-specific CAR-T cells is currently being tested in patients with HER2-positive solid tumors. (NCT03740256)
VCN-01: Based on Ad5, designed to carry integrin-binding polypeptide RGD to efficiently infect tumor cells, and treat tumors by expressing hyaluronidase to degrade extracellular matrix. Intratumoral (IT) injection of VCN-01 can reduce tumor growth and improve survival. The Phase I clinical trial of the combination of VCN-01 and Durvalumab monoclonal antibody for the treatment of relapsed/metastatic HNSCC is in progress. (NCT03740256)
OBP-301: Based on Ad5, the human telomerase reverse transcriptase (hTERT) gene promoter is inserted upstream of the E1 gene. The combination of OBP-301 and cisplatin in the treatment of HNSCC has an anti-tumor effect and can overcome the radiotherapy resistance of HNC.
02. Herpes simplex virus HSV
Herpes virus (HSV): a double-stranded DNA enveloped virus containing 152kb, encoding about 80 kinds of proteins, infects a wide range of hosts, and mainly attacks skin, mucous membranes and nerve tissues.
HF10: A naturally mutated HSV with no oncolytic transgene insertion or deletion. HF10 can replicate in HNSCC cells and kill HNSCC cells. By inducing tumor necrosis, infiltrating CD8 cells, and releasing anti-tumor cytokines (including IL-2, IL-12, TNF-α, IFN-α, -β and -γ), HF10 can inhibit tumor growth and growth in ear tumor models. Extend the life span.
ONCR-177: Based on HSV-1, insert five transgenes: IL-12 is used to activate natural killer cells (NK) and T cells, the extracellular domains of CCL4 and FLT3LG are used to expand and recruit DCs, PD-1 and CTLA -4 antagonists are used to overcome T cell senescence.
In order to reduce virus replication in normal cells and selectively target tumor cells, ONCR-177 also carries microRNAs used to degrade viral transcripts. A phase I clinical trial of ONCR177 and Pembrolizumab monoclonal antibody in the treatment of HNSCC patients is underway. (NCT04348916)
03. Vaccinia virus VV
Vaccinia virus (VV): A double-stranded DNA enveloped virus that can carry larger transgenes.
GL-ONC1 (GLV-1h68): Based on VV, the genes encoding thymidine kinase (TK), hemagglutinin (HA) and F145L are deleted, and the genes encoding β-galactosidase, β-glucuronidase and renin are inserted. Luciferase/green fluorescence (RLuc-GFP) gene. A phase I clinical trial showed that intravenous injection of GL-ONC1 combined with radiotherapy and chemotherapy can improve the overall and progression-free survival rate of HNC patients.
JX-594 (PexaVec): Based on VV, delete TK gene, insert GM-CSF gene and E. coli lac-Z. Phase I clinical trials for solid tumors including HNC are ongoing. (NCT00625456)
04. Measles virus (MV)
Measles virus (MV): a single negative-stranded RNA enveloped virus with a spirally symmetrical nucleocapsid and two spikes (HA and hemolysin) on the surface.
MV-NIS: Based on MV, insert thyroid sodium iodide transporter (NIS). In order to infect tumor cells, MV-NIS uses the CD46 receptor to fuse the infected cells with uninfected neighboring cells to form multinucleated syncytia to prevent proliferation. A phase I trial of intratumoral injection of MV-NIS for HNSCC patients is underway. (NCT01846091)
05. Coxsackie virus
Coxsackie virus: a single positive-stranded picorna virus.
CAVATAK (CVA21): Infects tumor cells by binding to intracellular adhesion molecule-1 (ICAM-1). A phase I trial of intratumoral injection of CAVATAK for HNC patients is underway. (NCT00832559)
06. Reovirus (REO)
Reovirus: Non-enveloped double-stranded segmented RNA virus. Due to the overexpression of the oncogene Ras and the damage of the type I interferon (IFN) signaling pathway, it can preferentially replicate in cancer cells.
Reolysin (Pelareorep): a natural oncolytic virus, derived from a virus-free strain of human reovirus serotype 3. Intravenous (IV) injection of REO in HNSCC patients has high safety and tolerability, and its combined application with paclitaxel/carboplatin has been in clinical phase II and phase III trials. (NCT00753038 and NCT01166542)
(The table is a summary of clinical trial information of various oncolytic viruses in the treatment of head and neck cancer)
Discussion on the difficulties of oncolytic viruses in the treatment of HNC: The pre-existing immunity hinders the systemic delivery of virus particles to tumor cells, resulting in a decrease in the efficiency of OVs. At present, the diffusion and penetration of OVs are enhanced through the use of polymer coatings, cell carriers, and immunosuppressive drugs.
B. Monoclonal antibody immunotherapy
Monoclonal antibodies (mAbs) are produced by specific B cell clones that bind to specific epitopes. Because of its multiple disease targets, monoclonal antibodies play an important role in the diagnosis and treatment of various cancers.
(The picture shows the structure of different mAbs)
Tumor angiogenesis requires a variety of stimulating factors, including fibroblast growth factor 2 (FGF2), transforming growth factor β (TGF β), epidermal growth factor receptor (EGFR), interleukin-8 (IL-8), angiogenesis , Hepatocyte Growth Factor (HGF) and Vascular Endothelial Growth Factor (VEGF).
The VEGF family is composed of placental growth factor (PlGF) and VEGF a~e. They are the key regulators of angiogenesis and play an angiogenic effect by binding to the VEGF receptor VEGFR1-3.
01. Monoclonal antibodies targeting angiogenesis
Bevacizumab: anti-VEGF-a monoclonal antibody. In phase III clinical trials, the combination of Bevacizumab monoclonal antibody and chemotherapy can improve progression-free survival (6.0 months vs. 4.3 months, P=0.0014) and remission rate (35.5% vs. 24.5%, P=0.016).
Ramucirumab: anti-VEGFR2 monoclonal antibody, excellent curative effect in the treatment of HNC and other solid tumors.
Ficlatuzumab: anti-HGF monoclonal antibody, combined with cetuximab to treat patients with relapsed/metastatic HNC has controllable safety and good anti-tumor activity.
Cetuximab: anti-EGFR monoclonal antibody, combined with radiotherapy can significantly improve the 5-year survival rate.
02. Monoclonal antibodies that suppress immune checkpoints
Monoclonal antibodies that inhibit immune checkpoints:
Anti-PD-1: Pembrolizumab, Nivolumab
Anti-PD-L1: Atezolizumab, Avelumab, Durvalumab
Anti-CTLA-4: Lpilimumab and Tremelimumab
(The table is a summary of clinical trial information of a variety of monoclonal antibodies for the treatment of head and neck cancer)
C. CAR-T cell immunotherapy
Chimeric Antigen Receptor (CAR)-T cell therapy is a targeted modification of patient T cells to precisely target tumor antigens and kill cancer cells. At present, the design structure of CAR-T cells has undergone five generations of updates, as shown in the following figure:
In HNSCC cases, ErbB antigens are generally up-regulated, which is associated with radioresistance, tumor metastasis and low survival rates. Combination therapy of CAR-T cells targeting ErbB and oncolytic viruses carrying immune checkpoint inhibitors can significantly improve the survival rate of HNSCC and control primary/metastatic tumors.
(The table is a summary of the clinical trial information of a variety of CAR-T cells for the treatment of head and neck cancer)
D. Therapeutic vaccine therapy
Therapeutic vaccines are different from preventive vaccines in that they can achieve therapeutic effects by inducing specific immune responses in the body that has been infected with pathogenic microorganisms or diseases. Various therapeutic vaccines have been developed for antigens or epitopes expressed in tumors.
01. Head and neck cancer vaccine targeting viral antigens
MEDI0457: DNA vaccine, containing three plasmids expressing HPV16/18 E6 and E7 proteins, and IL-12, which is effective for HPV-positive HNC tumors. The Phase 1b/2a clinical trial of combined Durvalumab monoclonal antibody is in progress. (NCT03162224)
ADXS11-001 (ADXS-HPV): Attenuated Listeria monocytogenes (Lm)-LLO for HPV16 E7. Clinical trials for the treatment of HPV-positive HNS are underway. (NCT02002182)
TG4001 and ISA101: Clinical trials of combined checkpoint inhibitors against HPV antigens are underway. (NCT03260023 and NCT02426892)
02. Head and neck cancer vaccine targeting TAA and TSA
MUC1 vaccine: A phase I clinical trial in combination with Tadalafil for the treatment of HNC is underway. (NCT02544880)
CEA vaccine (GI-6207): down-regulate the patient’s Tregs and increase CD4 and CD8 T cells, enhancing the immune response.
INO-1400/UCPVax: Targeting HTERT, combined with IL-12DNA and atezolizumab monoclonal antibody to treat HNC clinical trials are in progress. (NCT02960594 and NCT03946358)
03. Head and neck cancer vaccine targeting specific neoantigens
GEN-009: Clinical trials of combined immune checkpoint inhibitors pembrolizumab and nivolumab in the treatment of solid tumors are underway. (NCT03633110)
The immunotherapy strategy for head and neck cancer has attracted much attention in the past two decades, and it is also facing many challenges. In-depth study of the immune status and immune response intensity in the tumor microenvironment is essential for the design and application of tumor immunotherapy strategies.
In addition to choosing an appropriate treatment strategy, identifying predictive biomarkers for patient selection and predicting clinical response are also critical in cancer immunotherapy. Combining different strategies to combine therapy will improve the efficacy of tumor immunotherapy.
(source:internet, reference only)