Pilot Study of mRNA-zOX40L Treatment in dogs with solid tumors

Lipid nanoparticles have been used for the past few years as components in the now approved mRNA based COVID vaccines and have also been used in several cancer vaccine studies. A newer version of the LNP, called LNP A, have been shown to effectively transfect monocytes and macrophages (two important types of immune cells) in the blood and spleen and evidence suggests that they can directly get into tumors in several different mouse models. Based on this finding, it is hoped that the LNP A could be used to deliver mRNAs that code for proteins designed to activate an immune response in tumors. This would be extremely useful for targeting specific immune subsets (monocytes and macrophages) that are known to suppress immune system killing of cancers. In 
the current study, we will test the ability of an mRNA encodes mouse OX40L-D99K reporter protein (also called "zOX40L") to be expressed in canine immune cells and tumor cells. The zOX40L is a “dead” protein as it does not function, but it serves as a biomarker (indicator) that the mRNA has gotten into the cell and is expressed. Therefore, the primary objectiv of this study is to measure the expression of zOX40L protein in immune cells in the blood and tumor cells and immune cells within solid tumors from dogs following infusion with the zOX40L mRNA LNP A.

Inclusion Criteria

• Dogs diagnosed with cytologically or histologically confirmed spontaneous solid tumor are eligible for enrollment. The dog may have undergone prior surgical resection or there may be no other known effective therapeutic options, or the owner may elect to enter the dog in lieu of standard therapy.
• The tumor must be at least 1 cm and no larger than 7 cm in size
• Adequate organ function as indicated by standard laboratory tests (complete blood count, serum biochemistry profile, urinalysis).
  • ANC?1 000/μL and platelet count ? 100,000/μL
  • Liver: Total bilirubin ≤ 1.5X the institutional upper limit of normal 
    (ULN), ALT ≤ 3X ULN
  • ECOG performance score of 0-1
• Otherwise medically healthy with no clinically significant physical findings upon examination, medical history, and clinical laboratory profile, as deemed by the Principal Investigators.
• Dogs must have an estimated life expectancy of at least 2 months.
• Dogs may have received NSAIDs or steroids, but must be off all drugs that could impact the immune response for at least 7 days prior to enrollment.
• Informed written consent must be obtained  

Exclusion Criteria

• Pregnant or lactating dogs
• Dogs with solid tumors of hematopoietic origin (mast cell tumor, histiocytic sarcoma, plasma cell tumor, cutaneous lymphoma, etc.)
• Necrosis involving more than 10% of the visible tumor
• Evidence of metastatic disease to any organ including lungs
• Prior treatment with radiation therapy or chemotherapy
• Concurrent use of complementary or alternative medicines that in the opinion of the Principal Investigator would confound the interpretation of toxicities and/or antitumor activity within the context of this study.
• Dogs with significant liver or cardiovascular disease.
• Any serious systemic disorder incompatible with the Study (at the discretion of the PI).
• Use of any other investigational drug within 2 weeks of study entry.

Client Benefits

Screening for study enrollment (bloodwork and chest x-rays) will be covered by the study. You will receive a credit of $2000 toward the surgical removal of your dog's tumor. Should your dog develop a complication from the LNP A infusion, costs for treatment will be covered. Routine post-surgical complications (infection, etc.) are not covered by the study. 

Sample or Data Requirements

Your dog will undergo screening to ensure that he/she is a candidate for the study. Once enrolled, your dog will receive an infusion of the zCD40L over 1 hour. Your dog will then undergo removal of the tumor 24 hrs (1 day, study D2) or 72 hrs (3 days, study D4) after the infusion. A small amount of blood (10 ml, less than 1 tablespoon) will be drawn from your dog’s vein prior to surgical removal of his/her tumor. Should a local lymph gland be accessible we may use a needle to sample some cells from that location (needle aspiration) while your dog is under anesthesia for the tumor removal. After your dog’s tumor is removed, we will collect a portion of this tumor to collect and evaluate the immune cells and tumor cells that are in the tissue and to test for zCD409L expression.