Figure 6D. Effect of Lenti-HPV-07 immunotherapy on lung T cells in C57BL/6 with metastatic TC-1 tumors
Ontology highlight
ABSTRACT: C57BL/6 mice were injected i.v. with 1.5 × 10(5) nLuc-TC-1 cells. On day 5, mice received a single i.m. injection of 1.10(9) TU of Ctrl Lenti or Lenti-HPV-07 (n = 10-11/group). At day 15 post nLuc-TC-1 i.v. instillation, groups of untreated mice (Neg Ctrl) (n = 4) or Lenti Ctrl- (n = 10) or Lenti-HPV-07- (n = 10) treated and tumor bearing mice received an i.v. injection of PE-anti-CD45 mAb, 3 min before sacrifice ("CD45 i.v."). This in vivo staining allows cytometrical distinction of lung parenchymal (CD45i.v.-) from vascular (CD45i.v.+) hematopoietic cells. Lung T cells stained for cytometric analyses.
Project description:BackgroundSurgeons are increasingly asked to operate on patients with residual disease after immunotherapy. The safety and utility of lung resection in this setting are unknown.MethodsWe retrospectively reviewed patients who underwent lung resection within 6 months of treatment with checkpoint blockade agents for metastatic or unresectable cancer. Survival was estimated from the first resection using the Kaplan-Meier approach.ResultsDatabase query identified 19 patients who underwent 22 resections for suspected residual disease with therapeutic intent after immunotherapy between 2012 and 2016. Lung cancer was the most common diagnosis (47%), followed by metastatic melanoma (37%). The most frequently used agents were nivolumab (32%), pembrolizumab (32%), and ipilimumab (16%). Patients received a mean of 21 doses (range, 1 to 70 doses). The final dose was administered at an average of 75 days (range, 7 to 183 days) before the operation. Anatomic resection (lobectomy or greater) was performed in 11 patients (50%). Four lobectomies were attempted minimally invasively, and one required conversion to thoracotomy. Of the resected patients, 68% had viable tumor remaining. R0 resection was achieved in 95%. Mean operative time for lobectomy was 227 minutes (range, 150 to 394 minutes). Complications occurred in 32% of patients; all but 1 were minor (grade 1/2). The 2-year overall and disease-free survival were 77% and 42%, respectively.ConclusionsIn patients with previously metastatic or unresectable cancer, lung resection for suspected residual disease after immunotherapy is feasible, with high rates of R0 resection. Operations can be technically challenging, but significant morbidity appears to be rare. Outcomes are encouraging, with reasonable survivals during short-interval follow-up.
Project description:Radiotherapy is one of the mainstays of cancer treatment. More than half of cancer patients receive radiation therapy. In addition to the well-known direct tumoricidal effect, radiotherapy has immunomodulatory properties. When combined with immunotherapy, radiotherapy, especially high-dose radiotherapy (HDRT), exert superior systemic effects on distal and unirradiated tumors, which is called abscopal effect. However, these effects are not always effective for cancer patients. Therefore, many studies have focused on exploring the optimized radiotherapy regimens to further enhance the antitumor immunity of HDRT and reduce its immunosuppressive effect. Several studies have shown that low-dose radiotherapy (LDRT) can effectively reprogram the tumor microenvironment, thereby potentially overcoming the immunosuppressive stroma induced by HDRT. However, bridging the gap between preclinical commitment and effective clinical delivery is challenging. In this review, we summarized the existing studies supporting the combined use of HDRT and LDRT to synergistically enhance antitumor immunity, and provided ideas for the individualized clinical application of multimodal radiotherapy (HDRT+LDRT) combined with immunotherapy.
Project description:The presence of a tumor can alter host immunity systematically. The immune-tumor interaction in one site may impact the local immune microenvironment in distal tissues through the circulation, and therefore influence the efficacy of immunotherapies to distant metastases. Improved understanding of the immune-tumor interactions during immunotherapy treatment in a metastatic setting may enhance the efficacy of current immunotherapies. Here we investigate the response to αPD-1/αCTLA4 and trimAb (αDR5, α4-1BB, αCD40) of 67NR murine breast tumors grown simultaneously in the mammary fat pad (MFP) and lung, a common site of breast cancer metastasis, and compared to tumors grown in isolation. Lung tumors present in isolation were resistant to both therapies. However, in MFP and lung tumor-bearing mice, the presence of a MFP tumor could increase lung tumor response to immunotherapy and decrease the number of lung metastases, leading to complete eradication of lung tumors in a proportion of mice. The MFP tumor influence on lung metastases was mediated by CD8+ T cells, as CD8+ T cell depletion abolished the difference in lung metastases. Furthermore, mice with concomitant MFP and lung tumors had increased tumor specific, effector CD8+ T cells infiltration in the lungs. Thus, we propose a model where tumors in an immunogenic location can give rise to systemic anti-tumor CD8+ T cell responses that could be utilized to target metastatic tumors. These results highlight the requirement for clinical consideration of cross-talk between primary and metastatic tumors for effective immunotherapy for cancers otherwise resistant to immunotherapy.
Project description:BackgroundImmune checkpoint inhibitors have been demonstrated to improve overall survival. Atypical patterns of response have been reported, including dissociated response (DR). We evaluated the prevalence of DR.Patients and methodsPatients had to have a baseline computed tomography (CT) scan and at least one follow-up CT scan and two target lesions (TLs). Three types of DR were evaluated using RECIST1.1: DR1, defined as at least one progressive and one responding TL; DR2, defined as at least one progressive and one stable TL; and DR3, defined as at least one stable and one responding TL.ResultsA total of 1244 measurements of 272 TLs were performed in 100 patients. Forty-nine out of the 272 TLs (18%) had received old or recent radiotherapy, and 42 (15%) had been biopsied. An objective response was observed in 22 patients (22%) and on 52 TLs (19%). DR1 were observed in 8% of patients. At the tumor measurement level, the response rate was lower in the case of prior radiotherapy (29% vs 34%, p = 0.01) and higher in the case of prior biopsy (40% vs 32%, p = 0.02).ConclusionsA DR was observed in 8% of patients. Response rate was lower in the case of prior radiotherapy and higher in the case of prior biopsy.