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CV9201 is an RNActive ® -based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400-1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD + CD38 hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8-6.3) and 10.8 months (8.1-16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses., Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61)., Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions., Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors., Trial Registration: ClinicalTrials.gov identifier: NCT01915524 .

Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1)., Methods/design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments., Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients., Trial Registration: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41.

Objective: Patients with small cell lung cancer (SCLC) are frequently denied surgical treatment despite growing body of evidence for a longer duration of remission and overall survival, if surgical intervention is integrated in a tri-modality therapy concept including chemotherapy, surgery, and radiotherapy., Methods: A retrospective analysis was performed using data derived from 95 patients with SCLC operated upon over a period of 9 years. A subset of these patients was primarily operated upon and being diagnosed as SCLC only after thoracotomy, received radio-/chemotherapy postoperatively (n=64, group I). The second cohort had surgery after neoadjuvant chemotherapy which was continued postoperatively in addition to thoracic and cranial radiotherapy (n=31, group II). The patients in the second group were further divided into two subgroups: complete histological regression of tumor tissue in the mediastinal lymph nodes (group IIA), and those with persistent mediastinal lymph nodal involvement detected after thoracotomy (group IIB)., Results: Group I patients had stage I or II disease, whereas group II patients had clinical stage IIIA or IIIB. The overall 30-day mortality rate was as low as 5%. The median survival was 31.3 months for patients in group I, 31.7 months for adjuvant surgery with complete regression of mediastinal nodes (group IIA), and 12.4 months for adjuvant surgery without regression of mediastinal nodes (group IIB)., Conclusions: Surgical intervention is promising and warrants prospective trials to be evaluated as an important adjunct to multi-modality therapy regimen in SCLC as regards to its impact on relapse free and overall survival.

Objective: General acceptance in the oncologic community has been gained for combined modality treatment of non-small cell lung (NSCLC) cancer in locally advanced stage IIIA and IIIB disease. However, no optimal regimen has been established. This study (chemotherapy and radiochemotherapy followed by operation) assesses feasibility, response, resectability, and survival in patients with stage IIIA and IIIB lung cancer. Currently, only little data is available about the prognostic significance of tumor clearance of mediastinal nodes. Thus, an important aim of our study was to evaluate the prognostic significance of the extent of tumor reduction in mediastinal nodes by a neoadjuvant multimodality protocol., Patients: In a phase II protocol, 26 patients underwent neoadjuvant radiochemotherapy. Subsequently, a radical lymphadenectomy was performed during surgery. The extent of tumor regression was determined according to the methodology initially described by Salzer-Kuntschik for osteosarcoma: Grade I: no vital tumor cells, grade II: some tumor cells, grade III: less than 10 % vital tumor cells, grade IV: 10-50 % vital tumor cells, grade V: more than 50 % vital tumor cells, grade VI: no effect of chemotherapy., Results: Complete pathologic response was seen in 30.7 % of primary tumors, in 38.5 % of mediastinal lymph nodes, and in 23 % of corresponding specimens simultaneously. Median survival was 34.7 months for those patients with grade I, 12.6 months with grade II, and 8.9 months for patients showing a grade III/IV regression in mediastinal nodes. Response rate to neoadjuvant chemotherapy in mediastinal nodes proved to be the only statistically significant parameter for long-term survival: In cases with no vital tumor cells in the operation specimen, median survival was 34.7 months in comparison to those with vital cells showing a median survival of only 11.4 months (P = 0.01)., Conclusion: Patients with locally advanced NSCLCs can enjoy long-term survival after multimodal therapy. However, the complications related to therapy are considerably. Especially, clearance of tumor cells from mediastinal lymph nodes is an important independent prognostic factor.

Background: The relevance of a trimodal strategy in the treatment of lung cancer, consisting of neoadjuvant radiochemotherapy followed by surgery, is a subject of ongoing clinical trials. We tested whether improvement of long-term survival can be achieved for patients with stage III non-small cell lung cancer by this therapeutic approach., Methods: We performed a retrospective analysis of a single-institution phase II study. Of 33 patients enrolled in the protocol between 1992 and 1995, we reviewed the clinical outcomes of 26 patients with locally advanced non-small cell lung cancer (stage IIIA and IIIB), which had been resected after combined chemotherapy and radiochemotherapy., Results: After neoadjuvant therapy, resection of the tumor was accomplished in all patients, and R0 resection was achieved in 92%. Histologic remission was found in 76% of these patients. Involvement of mediastinal lymph nodes was crucially important for the outcome. First, histologic clearance of the mediastinal compartment by neoadjuvant therapy resulted in a 27% 5-year survival rate. Second, patients with viable tumor in any of the mediastinal lymph nodes removed had a poor outcome (median survival 11.4 and 34.7 months in patients with and without viable tumor cells in the specimens, respectively; p = 0.01)., Conclusions: Histopathologic regression after neoadjuvant multimodal therapy including chemotherapy and radiotherapy was an important prognostic factor in a selected group of patients with locally advanced lung cancer.

Purpose: About 40% of non-small cell lung cancer (NSCLC) patients are candidates for systemic chemotherapy, despite the fact that at diagnosis most NSCLC are usually chemoresistant both in vivo and ex vivo. It is important to develop sufficient methods of prediction of the response to chemotherapy and to find molecular markers that may prognose this response. Therefore, a study on the relationship of p53gene status to the ex vivo chemosensitivity of primary human NSCLC was performed., Methods: Three drug combinations (carboplatin/etoposide, cyclophosphamide/etoposide/epirubicin, and paclitaxel/carboplatin) were tested in a modified ATP cell viability assay. A group of 28 cases of primary human NSCLC was assessed., Results: Ex vivo chemosensitivity testing showed that tumors with p53 mutations were significantly more resistant to the cyclophosphamide/etoposide/epirubicin regimen than with normal p53 gene ( P = 0.012). However, no correlation was observed for two other treatment regimens., Conclusion: Mutations in the p53gene can lead to enhanced chemoresistance, confirming the hypothesis that the p53 gene may serve as a marker of tumor response to treatment in NSCLC. However, the data also illustrate that some additional factors might contribute to drug resistance of the examined tumors.

A pilot study on squamous cell lung carcinoma (LC) chemosensitivity in adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA) was performed. Besides the histological investigation, a modified ATP-CVA was used for the analysis of cancer cell chemosensitivity to four drug regimens, including topotecan, a promising agent for non-small-cell lung cancer (NSCLC) chemotherapy. Results of in vitro chemosensitivity testing showed chemoresistance or only weak response in the predominant amount of tumors.