Inclusion Criteria:

• Diagnosis of head and neck cancer that requires surgical resection

• Must have at least one lesion that is clinically accessible to RiMO-301 injection and amenable to receiving hypofractionated radiotherapy

• The selected target lesions must be measurable on cross-sectional imaging, and repeated measurements at the same location should be achievable

• Target tumor not in the previously irradiated field or in the field irradiated at least six months prior to RiMO-301 injection, and with no complications from the prior radiation course

• Patients must have recovered from acute toxic effects (≤ grade 1 CTCAEv6) of previous cancer treatments prior to enrollment

• Patients with locally advanced, resectable head and neck cancer:

  • suitable to receive a PD-1 inhibitor (pembrolizumab) as a standard of care in the discretion of the treating physician or Principal Investigator
  • suitable to receive hypofractionated radiotherapy as a standard of care in the discretion of the treating physician or Principal Investigator

• Have adequate bone marrow reserve:

  • Absolute neutrophil count ≥1.5x109 cell/L
  • Platelet count ≥100x109 cell/L
  • Hemoglobin at least ≥9.0 g/dL unless confirmed by treating physician as not posing any increased harm to patient and approved by Sponsor (transfusion is allowed to achieve hemoglobin of ≥9.0 g/dL 14-days prior to dosing)

• Have adequate liver function:

  • Total serum bilirubin no more than 1.5x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x ULN or ≤5.0x ULN in case of documented hepatic metastasis
  • Alkaline phosphatase ≤5x ULN

• Have a life expectancy of at least 12 weeks (in the opinion of the investigator)

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Females with childbearing potential should be using adequate contraceptive measures from the time of screening until 6 months after study discontinuation, should not be breastfeeding, and must have a negative pregnancy test prior to start of dosing

• Patients must sign a study-specific informed consent form prior to study entry.

Exclusion Criteria:

Diagnosis other than resectable, locally advanced head and neck cancers

• HPV associated head and neck cancer
• Nasopharynx head and neck cancer
• Have signs or symptoms of end-stage failure, major chronic illnesses other than cancer, or any severe concomitant conditions
• Symptomatic central nervous system metastases and/or carcinomatous meningitis
• Has received any approved or investigational anti-neoplastic agent or immunotherapy other than PD-1 inhibitors, pembrolizumab, within 4 weeks prior to RiMO-301 injection.
• Patients who are intolerant to pembrolizumab
• Active autoimmune disease that has required systemic treatment in the past 2 years
• Ongoing clinically significant infection at or near the incident lesion
• Major surgery over the target area (excluding placement of vascular access) ≤21 days from the beginning of the study drug or minor surgical procedures ≤7 days. No waiting is required following implantable port, enteral feeding tube, and catheter placement
• Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that would make the patient inappropriate for enrollment in this study
• Has any mental or medical condition that prevents the patient from giving informed consent or participating in the trial
• Pregnant and nursing women are excluded because of the potential teratogenic effects and potential unknown effects on nursing newborns
• Patients with a target lesion in the field that had complications from prior radiotherapy that are not amenable to repeat irradiation in the discretion of the treating physician or Principal Investigator
• Patients with lesions that have significant blood vessel involvement (such as carotid artery encasement) or other major structures