Introduction:

Merging chemo- and immunotherapy is a powerful treatment tactic against various cancers. However, a challenge arises when these treatments are paired: the cytotoxic effects of chemotherapy harm the activated immune system, weakening immunotherapy's potency. The utilization of local chemotherapy offers the potential to circumvent these adverse effects. Using immunological-cell-death (ICD) -inducing drugs, localized chemo treatment can spark the patient's immune defenses against cancerous cells and potentially prime the immune system against local and distal tumors. Yet, tumors are capable of modifying their microenvironment, allowing them to evade the immune response, leading to the need for immune checkpoint inhibitors (ICIs). Using iontronic devices for local chemotherapy lets us dispense chemotherapy locally, on-demand, for a specific duration. When coupled with ICIs, this method offers a chance to induce targeted cancer cell death during active periods and boost the influx of immune cells into the tumor during dormant times. [1],[2]

Aim:

This research delves into the intricacies of this combined therapy, introducing a new method, the controlled chemo-ICI treatment. This method fuses local chemotherapy with meticulous timing and ICIs, aiming to amplify immunogenic cancer cell death and uninterrupted immune reactions, all while reducing systemic strain. We expect this method to produce better therapeutic results than present techniques.

Methods:

In initial experiments, we utilize two ICD-inducing drugs: gemcitabine and oxaliplatin. We determined the cytotoxicity of these drugs on the murine KP lung cancer cell lines and actively delivered them through our iontronic devices. Subsequently, we want to plan to determine the drugs' capacity to induce ICD in vitro. Furthermore, we generated an ovalbumin-expressing KP (OVA-KP) cell line that elicits a regulated immune response in OT-1 cytotoxic T-cells. Utilizing the OVA-KP cell line, we plan on constructing a mouse model hosting OVA-KP tumors on both sides, mimicking human metastasis, where we will treat one of the tumors locally via the ionotronic pump and systemically via ICIs. Our next steps include observing tumor growth, survival, examining T-cell penetration into tumors post-treatment, and analyzing the T-cell subpopulations in the tumor. The focus will also extend to T-cells in peripheral lymphoid organs. Techniques such as immunohistochemistry (IHC) and flow cytometry will be employed to investigate these areas.

Expected Results:

The KP cell line is susceptible to both gemcitabine and oxaliplatin and reacts to the actively delivered treatment through the ionotronic device. The OVA-KP cell line triggers an immune response by the cytotoxic T-cells of the OT-1 model in vitro. We expect the flank model to exhibit reduced tumor growth in both the local and distal tumor, as well as enhanced immune cell infiltration in both local and distal tumors following both treatments, compared to vehicle treatment. We also generally expect to observe the hallmarks of an adaptive immune response, specifically through the activation of dendritic cells and the differentiation of T-cells into their active states. The co-treatment of the tumors with both the ionotronic pump and with ICIs should either enable or enhance the specific immune response to the tumors.