Treatment of Cancer with Immune Checkpoint Inhibition Therapy Boosted by High Intensity Focused Ultrasound Histotripsy

Inclusion Criteria:

1. Histologically confirmed metastatic or unresectable cancer that progressed understandard of care treatment options.

2. Age ≥ 18 years.

3. Has signed and dated written informed consent before performing any study procedure,including screening.

4. Anticipated life expectancy ≥ 12 weeks by investigator judgement.

5. At least one tumor lesion (primary tumor or metastasis) which is amenable toapplication of high intensity focused ultrasound histotripsy (determined by aradiologist with HIFU-expertise).

• The lesion must have a distance of ≤30 mm to the skin.

• At least part of the lesion must have a distance of ≥10 mm to the skin andother vulnerable structures (e.g. large blood vessels). This part should besufficient to be able to select at least one HT focus in an area of solidtumor.

• If the target lesion contains cystic or necrotic regions: the solid componentshould be ≥10 mm in diameter, sufficient to be able to select at least oneHIFU-HT focus in an area of solid tumor with ≥10 mm distance to the skin.

6. Sonication will be performed on tumors that have not previously directly beentreated with radiation therapy or surgery unless they showed significant massregrowth.

7. Measurable disease (at least one lesion besides the HIFU-HT treated lesion) on CTaccording to RECIST V 1.1 criteria (or on PET-CT according to PERCIST criteria) asassessed by investigator and local radiology review.

8. Performance status of 0 or 1 on the WHO Performance Scale.

9. Screening laboratory values must meet the following criteria:

• WBC ≥ 2.0x109/L,

• Neutrophils ≥1.5x109/L

• Platelets ≥100 x109/L

• Hemoglobin ≥5.5 mmol/L

• Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinineclearance ≥60 mL/minute (≤Grade 1)

• Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) ≤2.5 x ULN; AST/ALT <5 x ULN if liver involvement

• Serum bilirubin ≤1.5 x ULN or direct bilirubin ≤ULN for subjects with totalbilirubin levels >1.5xULN, except in subjects with Gilbert's Syndrome

10. Patients must agree to use an adequate method of contraception for the course of thestudy through 180 days after the last dose of study medication.

11. Patients must be willing to undergo tumor biopsy.

Exclusion Criteria:

1. Presence of known central nervous system, meningeal, or epidural metastatic disease.However, subjects with known brain metastases are allowed if the brain metastasesare stable for ≥4 weeks before the first dose of study treatment. Stable is definedas neurological symptoms not present or resolved to baseline, no radiologic evidenceof progression, and steroid requirement of prednisone ≤10 mg/day or equivalent.

2. Patients currently participating and receiving study therapy or patients whoparticipated in a study of an investigational agent and received study therapy orused an investigational device within 4 weeks prior to the first dose of the studytreatment.

3. Prior chemotherapy, targeted small molecule therapy or monoclonal antibodies within 4 weeks prior to the first dose of the study treatment.

4. Prior radiotherapy within 8 weeks prior to the first dose of the study treatment.The patient will be excluded from the study if the only targetable lesion hasdirectly been treated with radiation therapy in the past with an exception forlesions that showed massive regrowth.

5. Prior surgery or ablative therapy within 4 weeks prior to the first dose of thestudy treatment. The patient will be excluded from the study if the only targetablelesion has directly been treated with ablative therapy in the past.

6. Ongoing adverse events > Grade 1 due to a previously administered therapy. Subjectswith ≤ Grade 2 neuropathy, vitiligo, thyroid disorders, hypocortisolism or alopeciaof any grade are an exception to this criterion and may qualify for the study.

7. History of other malignancies, except adequately treated and a cancer-relatedlife-expectancy of more than 5 years.

8. Concurrent medical condition requiring the use of immunosuppressive medications, orimmunosuppressive doses of systemic or absorbable topical corticosteroids; exceedingprednisolone 10 mg or equivalent.

9. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, high-dose corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

10. Active infection requiring systemic therapy.

11. History of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

12. Known history of active Tuberculosis.

13. Receipt of a live vaccine within 4 weeks prior to the first dose of the studytreatment.

14. Hypersensitivity to any of the study drugs or their excipients.

15. Contra-indications to MR imaging (e.g. certain pacemakers or severe claustrophobia).Contra-indications to gadolinium-based contrast agents are not an exclusioncriterion, as a different brand of gadolinium can be used or if necessary the MRIcan be performed without contrast.

16. Pregnancy or lactation.

17. Any other medical or social condition that, in the opinion of the PrincipalInvestigator, might put the subject at risk of harm during the study or mightadversely affect the interpretation of the study data.