March PC-FACS

Abstract

March 2, 2022 Combined Chemotherapy and Anti-PD-1 Effect of Spiritual Care for Cancer Patients Mechanical Evaluation at EOL Effect of Identified Support on Older Populations Prescribing Antibiotics in Hospice Care Understanding Suicidal Self-Directed Violence Scopolamine Butylbromide to Prevent Death Rattle Rave Reviews Effects of Combined Treatment on Peripheral Neuropathy and Neuroinflammation Background: Chemotherapy-induced peripheral neuropathy (CIPN) is common and can affect patients’ long-term quality of life posttreatment.1–4 How does a program cell death protein-1 (PD-1) blockade impact CIPN development? Design and Participants: This study investigated the effects of monotherapy or co-therapy with the chemotherapeutic drug paclitaxel (associated with neurotoxicity, neuroinflammation, and CIPN) and immunotherapeutic drug anti-PD-1 (enhances the immune response against cancer cells) on pain hypersensitivity, neurite outgrowth, and immune cells in mice. Mice were randomized into control, paclitaxel, anti-PD-1, and paclitaxel+anti-PD-1 groups. Mice were injected intraperitoneally (days 0, 2, 4, 7, 9, and 11), using 5 mg/kg for paclitaxel (or vehicle control) and 12.5 mg/kg for anti-PD-1 (or IgG control). Behavioral (mechanical paw withdrawal thresholds [days -1, 20, and 27]) and tissue (collected days 28–30) analyses were performed. ANOVA and Fisher's exact test were used. Results: Mice (n = 6/group) treated with paclitaxel or co-therapy, but not with anti-PD-1 alone, exhibited increased hind paw mechanical sensitivity. Anti-PD-1 did not cause mechanical hypersensitivity or exacerbate paclitaxel-induced allodynia. However, both paclitaxel and anti-PD-1 reduced ex vivo neurite outgrowth of dorsal root ganglion (DRG) explants derived from treated mice, whereas only paclitaxel reduced the neurite outgrowth after direct in vitro treatment. Anti-PD-1 and co-therapy, but not paclitaxel, changed the T-cell profile in lymphoid organs and caused increased T-cell infiltration into the DRG. Paclitaxel and co-therapy increased DRG macrophage levels, and all treatments induced altered microglia marker expression in the dorsal horn of the spinal cord. Thus, both paclitaxel and anti-PD-1 induced neuroinflammatory and axonal degenerative effects; however, these were not cumulative in co-therapy. All P < 0.05. Commentary: Chemotherapy-induced peripheral neuropathy, observed in up to 80% of patients, can limit adherence to treatment and decrease quality of life.5,6 Although some treatments can be used for neuropathic pain, such as opioids or duloxetine, they are only partially effective. Immunotherapy is increasingly used for cancer treatment as monotherapy or in conjunction with chemotherapy. PD-1 and PD-L1 are expressed in the nervous system, including trigeminal ganglion, spinal dorsal horn, thalamic and cortical neurons,7 and blocking the PD-1 or PD-L1 pathway may unleash existing pain syndromes, induce allodynia,8–10 and suppress GABAergic neurotransmission in the spinal neurons.7 A recent systematic review found that combining chemotherapy and immune checkpoint inhibitors may increase the incidence of peripheral neuropathy in patients with solid tumors;11 however, the current study conducted in mice does not support that combination therapy increases CIPN. Bottom Line: Combination treatment with paclitaxel-anti-PD-1 did increase the severity of neuroinflammation and was associated with changes in spinal cord immunity with unclear significance. Reviewer: Regina M. Mackey, MD, Center for Palliative Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN.