by akronbiotech

With the FDA approval of Kymriah to treat B-cell acute lymphoblastic leukemia and Yescarta to treat B-cell lymphoma, immunotherapy for cancer is becoming increasingly common. These existing therapies are systemically delivered and are not necessarily tumor-specific. This systemic administration can have major side effects by stimulating the activity of the entire immune system, not just a local response. Surgery is the classic method of treating cancerous tumors, but surgery does not necessarily remove all the malignant cells. As a result, cancer tends to recur in patients who have undergone surgery to remove solid tumors and surgery cannot eradicate distant metastases.

To address these concerns, researchers at the Dana-Farber Cancer Institute designed hydrogel scaffolds that gradually released immune-stimulating drugs. These hydrogels were then implanted into mouse models at the sites of surgical tumor removal. Each hydrogel tested contained an immunostimulatory compound. Various compounds were tested, and prevention of local tumor recurrence was most effective when an agonist of innate immunity was administered via the hydrogel.

Extended local release of agonists of innate immunity prevents tumor recurrence and eliminates distal metastases. Tumors were resected from mice 10 days after orthotopic inoculation of 4T1-Luc2 cells, and hydrogels loaded with the following payloads were evaluated: anti–PD-1, anti-CTLA-4, IL-15sa, lenalidomide, celecoxib, STING-RR, or R848. Mice that did not receive a hydrogel were examined as a negative control. IVIS imaging of 4T1-Luc2 cells is shown for all groups described and illustrates tumor burden.

Furthermore, the hydrogel delivery mechanism was key to observed efficacy. Additional modes of administration (e.g. intravenous injection, intraperitoneal injection, local delivery in solution) and timing (e.g. single-dose, weekly) were compared to the controlled release hydrogel. The survival benefit was observed only when the agonist of innate immunity was delivered via the extended release hydrogel.

The extended release hydrogel therapy increased the numbers of activated natural killer (NK) cells, dendritic cells, and T cells and induced production of large amounts of type I interferons. Thus, the approach successfully converted the local immunosuppressive post-resection microenvironment into an immunostimulatory one, such that the immune system is prepared to fight cancer cells.

Altogether, this approach was safe and more effective than systemic or even local injection of immunotherapy. This therapy shows great promise to deliver immunotherapy in a spatiotemporally defined manner, allowing us to specifically direct therapy at the site of tumor resection following surgical removal.

The article, titled “Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases,” was published in Science Translational Medicine.



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