Photoimmunotherapy and Irradiance Modulation Reduce Chemotherapy Cycles and Toxicity in a Murine Model for Ovarian Carcinomatosis: Perspective and Results

Abstract

Significant toxicities from multiple cycles of chemotherapy often cause delays or early termination of treatment, leading to poor outcomes in ovarian cancer patients. Complementary modalities that potentiate the efficacy of traditional agents with fewer cycles and less toxicity are needed. Photodynamic therapy is a mechanistically-distinct modality that synergizes with chemo and biologic agents. A combination regimen with a clinically relevant chemotherapy cocktail (cisplatin + paclitaxel) and anti-EGFR targeted photoimmunotherapy (PIT) is evaluated in a murine model for ovarian carcinomatosis. Mice received either 1 or 2 chemotherapy cycles followed by PIT with a chlorine6-Erbitux photoimmunoconjugate and 25 J/cm2 light. PIT + 1 cycle of chemotherapy significantly reduced tumor burden, comparable to multiple chemotherapy cycles. Relative to 1 cycle of chemotherapy, the addition of PIT did not cause significant mouse weight loss, whereas 2 cycles of chemotherapy led to a significant reduction in weight. Irradiance-dependence on PIT efficacy was a function of the conjugation chemistry, providing an additional variable for optimization of PIT outcome.

Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates

“…Furthermore, taPIT enables a ∼17-fold increase in the maximum tolerated photodynamic dose compared with targeted, always-on immunoconjugates for PIT [0.5-1 mg·kg −1 photodynamic agent with 3-6 J·cm −1 per quadrant (21,23,40)]. Thus, taPIT enables unprecedented photodynamic doses for treating disseminated metastatic disease by overcoming nonspecific toxicities associated with-both targeted and nontargeted-alwayson agents.…”

“…5A; a second cycle added no significant benefit). As a further comparative benchmark, prior work indicates 10% and 50% tumor burden reduction for one and two cycles, respectively, of combination cisplatin plus paclitaxel chemotherapy-at the same doses used here (Materials and Methods)-in this mouse model of metastatic ovarian cancer (23). The relatively poor response to chemotherapy alone may be due to intrinsic resistance-the OVCAR5 cells used in this model have sevenfold resistance to cisplatin relative to a platinum-sensitive cell line (31) and contain a subpopulation of stem-like cells that are stimulated by chemotherapy (8).…”

“…Photodynamic therapy and PIT induce cytotoxicity using mechanisms that are distinct from traditional therapies (12)(13)(14) to overcome resistance (19,20,23) and stimulate, rather than suppress, antitumor immunity (14). For example, photodynamic action can trigger apoptosis through direct photodamage of Bcl-2 protein (13), which is a major cause of radioresistance and chemoresistance (45).…”

“…Levy and colleagues (18)-that has been shown to hold promise by us (19)(20)(21)(22)(23) and by others (18,24,25). Because photodynamic agents are mechanistically distinct from traditional treatment modalities (13,14), are effective against radioresistant and chemoresistant cells (19,20,26), and can also resensitize resistant cells to chemotherapy (20,23), the development of PIT is of importance for overcoming drug resistance.…”

“…Because photodynamic agents are mechanistically distinct from traditional treatment modalities (13,14), are effective against radioresistant and chemoresistant cells (19,20,26), and can also resensitize resistant cells to chemotherapy (20,23), the development of PIT is of importance for overcoming drug resistance. In fact, photodynamic therapy has been used in the treatment of disseminated peritoneal disease with some success intraoperatively (27) and endoscopically in the lung, bladder, and esophagus (SI Text, Note S1).…”