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

Gamma knife radiosurgery for recurrent trigeminal neuralgia.

OBJECT: Pain may fail to respond or may recur after initial gamma knife radiosurgery (GKS) for trigeminal neuralgia (TN). The authors examined their experience with performing a second GKS procedure in these patients. METHODS: Twenty-nine patients underwent repeated GKS for TN at our institution between March 1997 and March 2002. Questionnaires were mailed to patients to assess the degree of their pain relief and the extent of facial numbness. Nineteen patients responded. All patients underwent repeated GKS involving a single 4-mm isocenter directed at the trigeminal nerve as it exited the brainstem (mean maximum dose 23.2 Gy). At a mean follow up of 13.5 months after the second procedure, 10 patients (53%) were pain free and medication free. Four patients (21%) were pain free but elected to continue medication in reduced dose, and two patients (11%) had incomplete but satisfactory pain control and were still taking medication. There was new-onset facial numbness in eight patients (42%), rated as tolerable in all instances. CONCLUSIONS: Patients with facial numbness had a greater likelihood of being pain free than those with no sensory loss. The authors observed no cases of corneal anesthesia, keratitis, or deafferentation pain

Gamma knife radiosurgery for trigeminal neuralgia associated with multiple sclerosis.

OBJECT: The authors assessed the efficacy and complications from gamma knife radiosurgery (GKS) for multiple sclerosis (MS)-associated trigeminal neuralgia (TN). METHODS: There were 15 patients with MS-associated TN (MS-TN). Treatment involved three sequential protocols, 70 to 90-Gy maximum dose, using a single 4-mm isocenter targeting the ipsilateral trigeminal nerve at its junction with the pons with the 50% isodose. Pain was appraised by each patient by using Barrow Neurological Institute (BNI) Scores I through IV: I, no pain; II, occasional pain not requiring medication; IIIa, no pain but continued medication; IIIb, some pain, controlled with medication; IV, some pain, not controlled with medication; and V, severe pain/no pain relief. With a mean follow up of 17 months (range 6-38 months), 12 (80%) of 15 patients experienced pain relief. Three patients (20%) reported no relief (BNI Score V). For responders, the mean latency from treatment to the onset of pain relief was 13 days (range 1-61 days). Maximal relief was achieved after a mean latency of 56 days (range 1-157 days). Five patients underwent a second GKS after a mean interval of 534 days (range 231-946 days). The mean maximum dose at this second treatment was 48 Gy. The target was unchanged from the first treatment. All five patients who underwent repeated GKS improved. Complications were limited to delayed facial hypesthesias. Two (13%) of 15 patients experienced onset of numbness after the first GKS, as well as two of five patients following a second GKS. The patients found this mild and not bothersome. Each patient who developed hypesthesias also experienced complete pain relief. CONCLUSIONS: Gamma knife radiosurgery is an effective treatment for MS-TN. Radiosurgery carries an acceptable small risk of mild facial hypesthesias, and hypesthesia appears predictive of a favorable outcome

Evolution of postoperative pituitary adenoma resection cavities assessed by magnetic resonance imaging and implications regarding radiotherapy timing and modality

PURPOSE: This study evaluates the temporal evolution of the spatial relationship between the pituitary adenoma transsphenoidal surgical cavity and the adjacent optic chiasm and discusses implications on timing and choice of radiotherapy modality. METHODS: This retrospective observational review analyzed factors that might influence the postoperative relationship between the surgical cavity and the optic chiasm, including tumor type, craniocaudal tumor and resection cavity dimensions, the preoperative distance between tumor and the optic chiasm, the presence of cavernous sinus invasion, and the choice of intraoperative packing material. Changes observed on magnetic resonance imaging in the preoperative, immediate (within 72 h), and delayed (≥3 months) postoperative periods were compared. RESULTS: Sixty-five patient histories were analyzed. Preoperatively, the pituitary adenoma was apposed to the optic chiasm in 43 patients (66%). Postoperatively, 34 patients (52%) in the immediate postoperative period and 54 patients (83%) in the delayed postoperative period had a distance ≥2 mm between the resection cavity and the optic chiasm. This distance provides a greater margin of safety with adjuvant radiosurgery. Preoperative tumor size showed a strong association with postoperative descent of the optic chiasm. CONCLUSIONS: Preoperative tumor size and degree of mass effect on the optic chiasm predict postoperative changes. In this study, the distance between the resection cavity and the optic chiasm was greater at ≥3 months postoperatively than in the immediate postoperative period, regardless of preoperative mass effect, indicating radiotherapy planning should be deferred to ≥3 months postoperatively when not precluded by aggressive histological characteristics that necessitate more immediate treatment. PRECIS: To investigate the temporal relationship between the postoperative sellar surgical cavity and the adjacent optic apparatus after transsphenoidal resection of pituitary adenomas and the implications for radiotherapy

Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review.

Evolving interest in meningioma, the most common primary brain tumor, has refined contemporary management of these tumors. Problematic, however, is the paucity of prospective clinical trials that provide an evidence-based algorithm for managing meningioma. This review summarizes the published literature regarding the treatment of newly diagnosed and recurrent meningioma, with an emphasis on outcomes stratified by WHO tumor grade. Specifically, this review focuses on patient outcomes following treatment (either adjuvant or at recurrence) with surgery or radiation therapy inclusive of radiosurgery and fractionated radiation therapy. Phase II trials for patients with meningioma have recently completed accrual within the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer consortia, and Phase III studies are being developed. However, at present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma