Palliative Radiation Therapy for Vertebral Metastases and Metastatic Cord Compression in Patients Treated With Anti-PD-1 Therapy

Background: There is increasing use of immune checkpoint blockade (ICB) across multiple cancer types, including in patients at risk for vertebral metastases and cord compression. These patients are often treated with palliative radiotherapy (PRT); however, data evaluating the combination of PRT and ICB in patients with vertebral metastases is limited. Furthermore, patients with cord compression are generally excluded from prospective clinical trials. Therefore, we retrospectively evaluated outcomes following PRT and PD-1 inhibition in patients with vertebral metastases.Methods: We performed a retrospective chart review of 37 consecutive patients (total 57 lesions) treated with radiation for vertebral metastases who also received PD-1 inhibition. Patient, treatment and outcomes data were abstracted from the medical records.Results: Histologies included non-small cell lung cancer (n = 21), renal cell carcinoma (n = 9) and melanoma (n = 7). Out of 57 lesions,18 involved >1 segments of the vertebral column. There were isolated lesions in thoracic (16), lumbar (9), cervical (6), and sacral (8) vertebrae. Presenting symptoms included pain (19), numbness (10), and weakness (3). Eleven patients were asymptomatic. Radiologic cord compression was present in 12, epidural extension in 28 and compression fracture in 14. Eleven patients underwent surgical decompression prior to the onset of RT. Median radiation dose was 24 Gy (range 8–30 Gy). Stereotactic radiation was delivered in 4 patients; 33 patients received conformal RT. 21 patients received PD-1 inhibition after RT, 9 before RT and 7 with RT. Seven patients received concurrent CTLA-4 inhibitors with anti-PD-1 therapy.Treatment was in general well-tolerated. Toxicities included fatigue (6), transient pain flare (1), nausea/vomiting (1) and G1 skin changes (1). All patients reported some degree of pain relief. Numbness/weakness was improved in 6 of 13 patients with baseline symptoms (46%) and this was more likely in patients that received vertebral radiation after starting PD-1 inhibitors (71 vs. 17%, p = 0.04). Most patients (22 of 33 evaluable patients, 67%) had stability of irradiated lesions on subsequent follow up imaging performed at median of 30 days from RT, whereas 3 had a complete local response and 4 had a partial local response.Conclusions: We demonstrate that PRT administered to vertebral metastases was well-tolerated and effective in patients treated with PD-1 inhibitors. There was an encouraging rate of pain reduction and neurological improvement

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival