A promising avenue of clinical research in head and neck cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses.

Pembrolizumab (Keytruda®, MK-3475): A PD-1 Antibody

• A phase II trial for patients with surgically resectable head and neck cancer (NCT02296684). 
• A phase II trial for patients with head and neck cancer (NCT02289209).
• A phase II trial for patients with resected head and neck cancer (NCT02641093).
• A phase I/II study for patients with advanced cancer, including head and neck cancer (NCT02318901).
• A phase I/II trial for patients with recurrent head and neck cancer that is metastatic and/or cannot be removed with surgery (NCT02538510).
• A phase I/II trial for patients with advanced cancer, including head and neck cancer, combined with PLX3397, a tyrosine kinase inhibitor of KIT, CSF1R, and FLT3 (NCT02452424).
• A phase I trial for patients with head and neck cancer (NCT02586207).
• A phase I study for patients with head and neck cancer, in combination with a JAK inhibitor, INCB039110, or a PI3K-delta inhibitor, INCB050465 (NCT02646748).
• A phase I trial for patients with metastatic or advanced epithelial cancers, including head and neck cancer, in combination with enadenotucirev, an oncolytic virus (NCT02636036).
• A phase I study in patients with refractory cancer, including head and neck cancer, combined with MGA217, an antibody that targets B7-H3 (NCT02475213).
• A phase I trial for patients with recurrent or metastatic head and neck cancer (NCT02318771).

Durvalumab (MEDI4736): A PD-L1 Antibody +/- Tremelimumab: A CTLA-4 Antibody

• Two phase III trials of durvalumab +/- tremelimumab for patients with recurrent and/or metastatic head and neck cancer (NCT02551159, NCT02369874).
• A phase I/II trial of durvalumab for patients with advanced cancer, including head and neck cancer, with epacadostat (INCB024360), an IDO inhibitor (NCT02318277). IDO is expressed by a number of tumor types and correlates with poor prognosis.
• A phase I/II trial for patients with relapsed metastatic head and neck cancer, combined with AZD9150, an inhibitor of STAT3, or AZD5069, a chemokine receptor 2 (CXCR2) antagonist (NCT02499328).
• A phase I trial for patients with head and neck cancer, in combination with selumetinib, an inhibitor of MEK 1 and 2 (NCT02586987).

Nivolumab (Opdivo®): A PD-1 Antibody

• A phase II trial for patients with metastatic head and neck cancer (NCT02684253).
• A phase I/II trial for patients with solid tumors, including head and neck cancer, in combination with varlilumab (CDX-1127), an anti-CD27 antibody (NCT02335918).
• A phase I/II trial for patients with advanced cancer, including head and neck cancer, with epacadostat (INCB024360), an IDO inhibitor (NCT02327078). IDO is expressed by a number of tumor types and correlates with poor prognosis.
• A phase I trial for patients with advanced cancer, including head and neck cancer, in combination with FPA008, an antibody that inhibits colony stimulating factor-1 receptor (CSF1R), which targets immune cells (NCT02526017).

Other Drugs

• A phase I/II trial of monalizumab, which targets NKG2A receptors expressed on natural killer and T cells, for patients with head and neck cancer (NCT02643550).
• A phase I/II study of atezolizumab (MPDL3280A), a PD-L1 antibody, and varlilumab (CDX-1127), an anti-CD27 antibody, in patients with advanced cancer, including head and neck cancer (NCT02543645).  
• A phase I study of CPI-444, which targets the adenosine-A2A receptor that suppresses the anti-tumor activity of immune cells, +/- atezolizumab (MPDL3280A), a PD-L1 antibody, for patients with advanced cancer, including head and neck cancer (NCT02655822).  
• A phase I trial of PF-06801591, a PD-1 antibody, for patients with head and neck cancer (NCT02573259).
• A phase I trial of PF-04518600, an OX40 antibody, for patients with advanced cancer, including head and neck cancer (NCT02315066).
• A phase I trial of avelumab, a PD-L1 antibody, combined with PF-05082566, a 4-1BB antibody, for patients with advanced cancer, including head and neck cancer (NCT02554812).
• A phase I study to test ipilimumab (Yervoy®) combined with MGA217, an antibody that targets B7-H3, in patients with refractory cancer, including head and neck cancer (NCT02381314).
• A phase I trial of MEDI6469, an OX40 antibody, for patients with head and neck cancer (NCT02274155).
• A phase I study to test MGA217, an antibody that targets B7-H3, in patients with refractory cancer, including head and neck cancer (NCT01391143).
• A phase I study to test MGD009, a B7-H3 x CD3 DART protein, in patients with unresectable or metastatic B7-H3-expressing cancer, including head and neck cancer (NCT02628535).

Adjuvants are substances that are either used alone or combined with other immunotherapies to boost the immune response. Some adjuvant immunotherapies use ligands—molecules that bind to proteins such as receptors—to help control the immune response. These ligands can be either stimulating (agonists) or blocking (antagonists).

• Multikine (leukocyte interleukin, injection) is an investigational immunotherapeutic agent that is being tested in a phase III clinical trial as a potential first-line treatment for advanced primary head and neck cancer (NCT01265849). It is a preparation of synthetic interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-alpha, interferon gamma, and other immune-stimulating molecules.
• IRX-2 is prepared from the soluble factors secreted by stimulated leukocytes, which are rich in cytokines and other immune-activating molecules. One phase II trial is enrolling for head and neck cancer (NCT02609386).
• Poly-ICLC (Hiltonol®) is a Toll-like receptor 3 (TLR3) agonist. It is currently being tested in one phase II clinical trial for head and neck cancer (NCT02423863).
• VTX-2337 is a Toll-like receptor 8 (TLR8) agonist. It is currently being tested in one phase I clinical trial for head and neck cancer (NCT02124850).

Adjuvant immunotherapies with checkpoint inhibitors:

• A phase I/II trial of durvalumab, a PD-L1 antibody, for patients with advanced cancer, including head and neck cancer, with epacadostat (INCB024360), an IDO inhibitor (NCT02318277). IDO is expressed by a number of tumor types and correlates with poor prognosis.
• A phase I/II trial of nivolumab (Opdivo®), a PD-1 antibody, for patients with advanced cancer, including head and neck cancer, with epacadostat (INCB024360), an IDO inhibitor (NCT02327078).
• A phase I trial of nivolumab (Opdivo®) for patients with advanced cancer, including head and neck cancer, in combination with FPA008, an antibody that inhibits colony stimulating factor-1 receptor (CSF1R), which targets immune cells (NCT02526017).
• A phase I study of CPI-444, which targets the adenosine-A2A receptor that suppresses the anti-tumor activity of immune cells, +/- atezolizumab (MPDL3280A), a PD-L1 antibody, for patients with advanced cancer, including head and neck cancer (NCT02655822).  

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens.

• ADXS11-001 (ADXS-HPV) is currently being tested in a phase I head and neck cancer clinical trials (NCT02002182). ADXS-HPV is a human papillomavirus-based vaccine that has received an Orphan Drug Designation from the FDA.

Another major avenue of immunotherapy for head and neck cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Several trials of adoptive T cell transfer techniques are currently under way for patients with head and neck cancer, including:

• A phase I trial of chimeric antigen receptor (CAR) T cell transfer for patients with head and neck cancer (NCT01818323).
• A phase I study of T cells engineered to recognize the NY-ESO-1 marker (TBI-1301) in patients with solid tumors, including head and neck cancer (NCT02366546). NY-ESO-1, a tumor-associated antigen, is not found on normal cells, with the exception of the testis.
• A phase I trial of T cells engineered to recognize HPV-16 and -18 in patients with relapsed HPV-associated cancers, including head and neck cancer (NCT02379520).
• A phase I study of T cells engineered to recognize the NY-ESO-1, MAGE-A4, PRAME, survivin, and SSX markers in patients with solid tumors, including head and neck cancer (NCT02239861).

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.

• A phase I trial of MM-151, an EGFR antibody, and MM-121, an ErbB3 antibody, for patients with head and neck cancer (NCT02538627).

Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.

• A phase I trial of enadenotucirev, an oncolytic virus, for patients with metastatic or advanced epithelial cancers, including head and neck cancer, in combination with pembrolizumab (Keytruda®) (NCT02636036).

Cytokines are messenger molecules that help control the growth and activity of immune system cells.

• A phase I trial of interleukin 15 (IL-15) for patients with metastatic cancers, including head and neck cancer (NCT02452268).