Mesenchymal Stem Cells for Radiation-induced Xerostomia (MESRIX) in Previous HPV-positive Oropharyngeal Head and Neck Cancer Patients - A Safety and Feasibility Study

Design Randomized, controlled trial with blinding. To maintain allocation concealment all participants, care givers, trial investigators and outcome assessors except the Blood Bank staff will be blinded to the intervention. Staff from the Blood Bank will not have direct contact with the patients (hereafter the participants) as such.

Project plan For inclusion in the study participants will have their usual medical history taken according to guidelines from the Ear, Nose and Throat Surgical Department, Copenhagen University Hospital Rigshospitalet.

All participants will undergo a mini lip-suction, from which MSCs will be ex vivo expanded in a good manufacturing practice (GMP)-approved clean room facility (The Blood Bank, section 2014). When the cells arrive at the Blood Bank, participants will be randomized to either ex vivo expansion of their mesenchymal stem cells or having them frozen for potential later use. Expected ex vivo expansion phase is 3-4 weeks. The purification and isolation will be based on a protocol previously approved for clinical use.

Amount of MSCs required for injection Based on published animal studies the amount given for xerostomia to mice varies from 2 x 105 to 2 x 106 [19]. To convert these mice data to a realistic dose in humans we have extrapolated based on the following data: The volume density of submandibular glands very closely approximates 1 (1.06-1.07 mg/mm3) [27]. In the mice studies on radiotherapy the mean gland weight was approximately 350mg, which corresponds to an approximate volume of 350mm3. Therefore the mouse dose pr. gland volume is approximately 286.000-2.860.000cells pr. cm3 gland (when calculated from either 1 x 105 to 1 x 106). The volume of the submandibular gland in human subjects after radiotherapy is 6.6-7.9cm3 [28]. This corresponds to an approximate dose pr. patient of between 1.9 x 106 to 2.2 x 106, or 1.9 x 107 to 2.2 x 107 cells pr. submandibular gland. From the above assumptions and in order not to give to few cells we have chosen to proceed with the maximum dose corresponding to 2.8*10^6 MSC/cm^3 gland, i.e. a maximum total dose per patient of approximately 4,6 * 10^7 MSCs. However to standardize the dose given to patients, the amount given will be standardized to the size of their submandibular glands, as described below.

Injection of MSCs into submandibular glands Subjects will go to the ENT-department, section 2073 for inpatient procedures. The surgical procedure is done under local anaesthesia using ultrasonic guidance and sterile technique. After receiving the MSC-suspension or placebo-suspension, the surgeon will identify the submandibular glands and inject the suspension MSCs. Calculation of injected number of MSCs pr. participant rests on the following calculation: , where volume is the volume of the submandibular gland, and a gland-volume of app. 7-8cm3 is the norm. Therefore the amount of cells given to each participant will be app. in total. Afterwards the participant will be given a band-aid and over the counter analgesics. The MSCs will be suspended in Isotonic NaCl (0,9 mg/ml) and Human Albumin (HA) 1% to a final volume of 2ml. Placebo will be 2ml of Isotonic NaCl (0,9mg/ml) and HA 1%.