Tumors Resistant to Checkpoint Inhibitors Can Become Sensitive after Treatment with Vascular Disrupting Agents

Abstract

<jats:p>Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5–50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5–25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear.</jats:p>

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…As mentioned in the Introduction, effective treatment with VDAs will likely require combination therapy, specifically to overcome the peripheral surviving tumor tissue ring observed in most studies [ 11 , 41 , 56 , 258 ]. Imaging should be particularly effective in facilitating optimal combination based on timing and extent of acute vascular changes.…”

“…While the tumor center may necrose, the rim often repopulates rapidly. As such, several VDAs have been tested in combination with additional therapies [ 11 , 41 ], including radiotherapy [ 41 , 42 , 43 , 44 , 45 , 46 ], antiangiogenic agents (such as bevacizumab) [ 47 , 48 ], traditional cytotoxic chemotherapy (e.g., carboplatin, paclitaxel) [ 41 , 49 , 50 , 51 , 52 , 53 , 54 ] and recently immunotherapy [ 55 , 56 ]. There is a current resurgence of interest in VDAs and frequent reports describe novel agents, many based on the colchicine/combretastatin motif [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] ( Figure 2 A).…”

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

“…While the tumor center may necrose, the rim often repopulates rapidly. As such, several VDAs have been tested in combination with additional therapies, including radiotherapy [ 22 , 23 ], antiangiogenic agents (such as bevacizumab) [ 24 ] and, recently, immunotherapy [ 25 ]. There is a current resurgence of interest in VDAs, and frequent reports describe novel agents, many based on the combretastatin motif [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], including benzosuberenes [ 37 , 38 , 39 , 40 ].…”

Therapeutic Modification of Hypoxia

“…Allowing animals to breathe 60% oxygen rather than air (21%) was shown to decrease the levels of tumour hypoxia and immunosuppressive molecules, while also weakening immunosuppression of regulatory T-cells and increasing proinflammatory cytokines; these effects were associated with inhibition of tumour growth, decreased metastasis and prolonged animal survival [83]. In addition, treating tumours with vasculartargeting agents that effectively killed hypoxic cells could convert tumours that were unresponsive to checkpoint inhibitors into responders [87].…”