Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: A 20-year systematic review and meta-analysis.

BACKGROUND: Therapeutic cancer vaccination is an area of interest, even though promising efficacy has not been demonstrated so far. DESIGN: A systematic review and meta-analysis was conducted to evaluate vaccines' efficacy on breast cancer (BC) and ovarian cancer (OC) patients. Our search was based on the PubMed electronic database, from 1st January 2000 to 4th February 2020. OBJECTIVE: response rate (ORR) was the primary end-point of interest, while progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Analysis was performed separately for BC and OC patients. Pooled ORRs were estimated by fixed or random effects models, depending on the detected degree of heterogeneity, for all studies with more than five patients. Subgroup analyses by vaccine type and treatment schema as well as sensitivity analyses, were implemented. RESULTS: Among 315 articles initially identified, 67 were eligible for our meta-analysis (BC: 46, 1698 patients; OC: 32, 426 patients; where both BC/OC in 11). Dendritic-cell and peptide vaccines were found in more studies, 6/10 BC and 10/13 OC studies, respectively. In our primary BC analysis (21 studies; 428 patients), the pooled ORR estimate was 9% (95%CI[5%,13%]). The primary OC analysis (12 studies; 182 patients), yielded pooled ORR estimate of 4% (95%CI[1%,7%]). Similar were the results derived in sensitivity analyses. No statistically significant differences were detected by vaccine type or treatment schema. Median PFS was 2.6 months (95% confidence interval (CI)[1.9,2.9]) and 13.0 months (95%CI[8.5,16.3]) for BC and OC respectively, while corresponding median OS was 24.8 months (95%CI[15.0,46.0]) and 39.0 months (95%CI[31.0,49.0]). In almost all cases, the observed toxicity was only moderate. CONCLUSION: Despite their modest results in terms of ORR, therapeutic vaccines in the last 20 years display relatively long survival rates and low toxicity. Since a plethora of different approaches have been tested, a better understanding of the underlying mechanisms is needed in order to further improve vaccine efficacy.

Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 - 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach.

Cancer Immunotherapy: A Simple Guide for Interventional Radiologists of New Therapeutic Approaches.

The therapeutic options in the treatment of cancer therapy have been recently significantly increased with systemic immune-targeted therapies. Novel immunotherapy approaches based on immune checkpoint blockade or engineered cytotoxic T lymphocytes have reached late-stage clinical development, with highly encouraging results. The success of cancer immunotherapy has generated a tremendous interest in further developing and exploring these strategies in combination with other approaches such as radiotherapy and local ablative therapies in oncology. The goal of this review is to discuss current approaches in immunotherapy and provide simple and constructive explanations on their mechanisms of action as well as certain more common and serious toxicities.

Tumour endothelial marker 1/endosialin-mediated targeting of human sarcoma.

BACKGROUND: Tumour endothelial marker 1 (TEM1/endosialin/CD248) is a tumour-restricted cell-surface protein expressed by human sarcomas. We previously developed a high-affinity human single-chain variable fragment (scFv)-Fc fusion protein (78Fc) against TEM1 and demonstrated its specific binding to human and mouse TEM1. PATIENT AND METHODS: Clinical sarcoma specimens were collected between 2000 and 2015 at the Hospital of the University of Pennsylvania, as approved by the institutional review board and processed by standard formalin-fixed paraffin embedded techniques. We analysed TEM1 expression in 19 human sarcoma subtypes (n = 203 specimens) and eight human sarcoma-cell lines. Near-infrared (NIR) imaging of tumour-bearing mice was used to validate 78Fc binding to TEM1+ sarcoma in vivo. Finally, we tested an immunotoxin conjugate of anti-TEM1 78Fc with saporin (78Fc-Sap) for its therapeutic efficacy against human sarcoma in vitro and in vivo. RESULTS: TEM1 expression was identified by immunohistochemistry in 96% of human sarcomas, of which 81% expressed TEM1 both on tumour cells and the tumour vasculature. NIR imaging revealed specific in vivo targeting of labelled 78Fc to TEM1+ sarcoma xenografts. Importantly, 78Fc-Sap was effective in killing in vitro TEM1+ sarcoma cells and eliminated human sarcoma xenografts without apparent toxicity in vivo. CONCLUSION: TEM1 is an important therapeutic target for human sarcoma, and the high-affinity TEM1-specific scFv fusion protein 78Fc is suitable for further clinical development for therapeutic applications in sarcoma.

Opportunities in immunotherapy of ovarian cancer.

Ovarian cancer (OC) is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival, the 5-year survival rates remain ominously low at 45%. Novel therapies are urgently needed. The presence of T cells in the OC tumor microenvironment is correlated with improved progression-free and overall survival, while the presence of regulatory T cells and expression of T-cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy could hold promise in improving the treatment of OC. In this review, we will discuss the rational of immunotherapy, highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and summarize the immune effects of selected chemotherapeutic and radiotherapeutic agents.