Development of immune polarizing intratumoral drug delivery technologies

All over the world, people are being diagnosed with cancer or know someone who is, and despite the growing pool of treatment strategies, cancer remains among the deadliest diseases globally. Radiation therapy, chemotherapy, and surgery have been the standard of care for many years, but during the past decades, significant advances have been made, introducing new treatment options, including immunotherapy. One approach to cancer immunotherapy is priming the immune system to reverse immunosuppression in the tumor microenvironment (TME) and improve anticancer immunoreactivity. Unfortunately, immune stimulants are often associated with toxicity at subtherapeutic dose levels. Additionally, immune cells in the TME are plastic and reactive and require continuous stimulation. Thus, a drug delivery system, CarboCell, was developed within the group to safely deliver a Toll-like receptor 7/8 agonist and a transforming growth factor β inhibitor. CarboCell is a liquid that, upon intratumoral injection, creates a depot at the injection site, allowing sustained release of immunostimulatory drugs selectively within the TME.
The overall aim of this thesis was to provide a preclinical evaluation of intratumoral treatment with CarboCell immunotherapy. Accordingly, we demonstrated that intratumoral treatment with combinatorial CarboCell therapy led to impressive therapeutic efficacy across preclinical cancer models without compromising tolerability. CarboCell immunotherapy further activated the innate and adaptive immune system and had a substantial benefit on the systemic anticancer response and metastasis formation in the lungs.
These results prompted us to hypothesize that CarboCell treatment could augment the therapeutic performance of T cells leading to an investigation of the role of T cells in the CarboCell-mediated anticancer immune response. Here, we saw that T cells play an important role in CarboCell-mediated tumor control as long-term efficacy was absent in mice lacking T cells.
Adoptive T cell transfer (ACT) has shown impressive efficacy in hematological cancers and malignant melanoma, but efficacy in other solid tumors has been disappointing. It has been suggested that this is due to various reasons, including an immunosuppressive TME and a hindered infiltration of the adoptively transferred T cells to the tumor. We, therefore, hypothesized that intratumoral treatment with CarboCell immunotherapy could improve the infiltration of adoptively transferred T cells to the tumor and create better conditions for the cells after transfer. However, in most evaluated treatment regimens, CarboCell did not improve the infiltration of adoptively transferred T cells to the tumor bed, and the therapeutic efficacy was only slightly improved when CarboCell was combined with ACT.
In conclusion, the CarboCell drug delivery technology allowed for safe administration of a Toll-like receptor 7/8 agonist and a transforming growth factor β inhibitor and was capable of activating the innate and adaptive immune systems and creating impressive anticancer immune responses.