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Metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) have a chance of long-term survival and potential cure after hepatic metastasectomy. However, the appropriate postoperative treatment strategy is still controversial. The CELIM and FIRE-3 studies demonstrated that secondary hepatic resection significantly improved overall survival. The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen-specific cancer vaccine tecemotide (L-BLP-25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study were analyzed for efficacy outcomes based on patient characteristics, treatment and surveillance after surgery. In LICC, 40/121 (33%) patients, in CELIM 36/111 (32%) and in FIRE-3-LLD 29/133 (22%) patients were secondarily resected, respectively. Of those, 31 (77.5%) patients in LICC and all patients in CELIM were R0 resected. Median disease-free survival after resection was 8.9 months in LICC, 9.9 months in CELIM. Median overall survival in secondarily resected patients was 66.1 months in LICC, 53.9 months in CELIM and 56.2 months in FIRE-3-LLD. Median age was about 5 years less in LICC compared to CELIM and FIRE-3. Secondarily resected patients of LICC, CELIM and FIRE-3 showed an impressive median survival with a tendency for improved survival for patients in the LICC trial. A younger patient cohort but also more selective surgery, improved resection techniques, deep responses and a close surveillance program after surgery in the LICC trial may have had a positive impact on survival. This article is protected by copyright. All rights reserved.

Background Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. Methods HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. Results No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. Conclusion Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

Introduction Although chemoradiotherapy (CRT) is the standard of care for patients with unresectable stage III non–small-cell lung cancer (LA-NSCLC), most patients relapse. Tecemotide is a MUC1 antigen-specific cancer immunotherapy vaccine. Bevacizumab improves survival in advanced nonsquamous (NS)-NSCLC and has a role in immune modulation. This phase II trial tested the combination of tecemotide and bevacizumab following CRT in patients with LA-NSCLC. Patients and Methods Subjects with stage III NS-NSCLC suitable for CRT received carboplatin/paclitaxel weekly + 66 Gy followed by 2 cycles of consolidation carboplatin/paclitaxel ≤ 4 weeks of completion of CRT (Step 1). Patients with partial response/stable disease after consolidation therapy were registered onto step 2, which was 6 weekly tecemotide injections followed by every 6 weekly injections and bevacizumab every 3 weeks for up to 34 doses. The primary endpoint was to determine the safety of this regimen. Results Seventy patients were enrolled; 68 patients (median age, 63 years; 56% male; 57% stage IIIA) initiated therapy, but only 39 patients completed CRT and consolidation therapy per protocol, primarily owing to disease progression or toxicity. Thirty-three patients (median age, 61 years; 58% male; 61% stage IIIA) were registered to step 2 (tecemotide + bevacizumab). The median number of step 2 cycles received was 11 (range, 2-25). Step 2 worst toxicity included grade 3, N = 9; grade 4, N = 1; and grade 5, N = 1. Grade 5 toxicity in step 2 was esophageal perforation attributed to bevacizumab. Among the treated and eligible patients (n = 32) who were treated on step 2, the median overall survival was 42.7 months (95% confidence interval, 21.7-63.3 months), and the median progression-free survival was 14.9 months (95% confidence interval, 11.0-20.9 months) from step 1 registration. Conclusions This cooperative group trial met its endpoint, demonstrating tolerability of bevacizumab + tecemotide after CRT and consolidation. In this selected group of patients, the median progression-free survival and overall survival are encouraging. Given that consolidation immunotherapy is now a standard of care following CRT in patients with LA-NSCLC, these results support a role for continued investigation of antiangiogenic and immunotherapy combinations in LA-NSCLC.

Background and Objective: We performed this systematic review and meta-analysis to assess the efficacy and safety of antigen-specific immunotherapy (Belagenpumatucel-L, MAGE-A3, L-BLP25, and TG4010) in the treatment of patients with non-small-cell lung cancer (NSCLC). Methods: A comprehensive literature search on PubMed, Embase, and Web of Science was conducted. Eligible studies were clinical trials of patients with NSCLC who received the antigenspecific immunotherapy. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), progression-free survival (PFS). Pooled risk ratios (RRs) were calculated for overall response rate (ORR) and the incidence of adverse events. Results: In total, six randomized controlled trials (RCTs) with 4,806 patients were included. Pooled results showed that, antigen-specific immunotherapy did not significantly prolong OS (HR=0.92, 95%CI: 0.83, 1.01; P=0.087) and PFS (HR=0.93, 95%CI: 0.85, 1.01; P=0.088), but improved ORR (RR=1.72, 95%CI: 1.11, 2.68; P=0.016). Subgroup analysis based on treatment agents showed that, tecemotide was associated with a significant improvement in OS (HR=0.85, 95%CI: 0.74, 0.99; P=0.03) and PFS (HR=0.70, 95%CI: 0.49, 0.99, P=0.044); TG4010 was associated with an improvement in PFS (HR=0.87, 95%CI: 0.75, 1.00, P=0.058). In addition, NSCLC patients who were treated with antigen-specific immunotherapy exhibited a significantly higher incidence of adverse events than those treated with other treatments (RR=1.11, 95%CI: 1.00, 1.24; P=0.046). Conclusion: Our study demonstrated the clinical survival benefits of tecemotide and TG4010 in the treatment of NSCLC. However, these evidence might be limited by potential biases. Therefore, further well-conducted, large-scale RCTs are needed to verify our findings.

Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients.A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life.We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone.Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) (P = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm (P = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome. EudraCT No: 2011–000218-20 Clinical Trial Information: NCT01462513 Financial Support: Merck KGaA, Darmstadt, Germany Abbreviations AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus.

Background: Immune-based therapeutic strategies represent a promising approach in early and advanced breast cancer treatment. MUC1 glycoprotein is overexpressed and aberrantly glycosylated in over 90% of malignant breast cancer. It is involved in oncogenesis and confers resistance to anti-cancer therapies, thus representing a particularly promising target. Tecemotide is a MUC1-based therapeutic cancer vaccine. The aim of this trial was to investigate the efficacy and safety of preoperative tecemotide in primary breast cancer patients receiving neoadjuvant Standard-of-Care (SoC) treatment. Patients and Methods: 400 patients with HER2-negative early breast cancer were recruited into this prospective, multicentre randomized 2-arm academic phase-II trial. Patients received preoperative SoC treatment with or without tecemotide therapy. Postmenopausal women with E+++, or E++ and Ki67 Results: We did not observe a significant difference in RCB0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40), and in endocrine and chemotherapy treated subgroups (25.0% vs 13.3%, p = 0.17; 39.6% vs 37.8%, p = 0.75). Similarly, addition of tecemotide did not affect overall pCR rates (22.5% vs 17.4%, p = 0.23). RCB0/I rates were comparable regardless of docetaxel being given before or after epirubicin/cyclophosphamide (37.2% vs 40.1%, p = 0.61). Tecemotide addition was not associated with a worse toxicity profile (178 AEs, 57 SAEs vs 180 AEs, 48 SAEs based on patient incidence). Conclusion: Immune-based targeting of MUC1 by tecemotide is safe but does not improve RCB and pCR rates in early SoC-treated breast cancer. Citation Format: Singer CF, Pfeiler G, Hubalek M, Bartsch R, Stoeger H, Pichler A, Petru E, Greil R, Rudas M, Tea M-KM, Wette V, Petzer AL, Sevelda P, Egle D, Dubsky PC, Balic M, Tinchon C, Bago-Horvath Z, Frantal S, Michael G. Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomized, neoadjuvant phase-II study (ABCSG-34) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-10-01.

Purpose of review Despite aggressive treatment based on definitive chemoradiotherapy, 5-year overall survival in unresectable stage III nonsmall cell lung cancer remains poor (15-20%). The novel immunotherapy based on immune checkpoint inhibitors (ICIs) presents as the therapeutic 'Holly Grail' in lung cancer treatment. Recent findings Preclinical models provide evidence of immunotherapy-radiotherapy (IM-RT) synergy. The exposure to ionizing radiation turns tumor in an in-situ vaccine, primes the innate immune system, increases immunotherapy efficacy by overcoming the immunosuppressive microenvironment of immune-resistant tumors and promotes a systemic, out-of-field antitumor T-cell-mediated response called abscopal effect. The immunomodulatory and abscopal effects of radiotherapy can be further enhanced by combining with systemic immunotherapies. The phase III START trial proved that liposomal vaccine - tecemotide (L-BLP25) administered as maintenance therapy after concurrent chemoradiotherapy (CRT) in LA-NSCLC prolongs survival. In the phase III PACIFIC trial consolidation with durvalumab, an anti-PDL-1 antibody, was associated with survival benefit in patients diagnosed with LA-NSCLC who responded to concurrent chemoradiotherapy. Summary PACIFIC trial results are expected to definitely establish durvalumab as standard consolidation strategy in LA-NSCLC. Many clinical trials are ongoing in the field of immunoradiotherapy in LA-NSCLC to define the optimal conditions for this therapeutic combination.

Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC.

The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1. Designed to target tumor associated MUC1, tecemotide is being evaluated in Phase III clinical trials for treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) as maintenance therapy following chemoradiotherapy. Additional Phase II studies in other indications are ongoing. This review discusses the preclinical and clinical development of tecemotide, ongoing preclinical studies of tecemotide in human MUC1 transgenic mouse models of breast and lung cancer, and the potential application of these models for optimizing the timing of chemoradiotherapy and tecemotide immunotherapy to achieve the best treatment outcome for patients.

Purpose To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non–small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. Patients and Methods Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 μg). Subsequent immunizations were administered at 6-week intervals. Results The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. Conclusion L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

Background: There is increasing interest in using combination immunotherapy in the neoadjuvant setting in prostate cancer, however, endpoints for such studies remain elusive. We have conducted a clinical trial evaluating immunotherapy with ADT in patients with high risk prostate cancer. Patients were assessed for immune responses and changes in endorectal (er) MRI which can be used to assess intraprostatic tumors. Methods: Treatment-naïve high-risk (Gleason 8-10, PSA>20, or stage T3) prostate cancer patients (pts) were randomized to standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25) in this trial (NCT01496131). ADT consisted of gonadotropin-releasing hormone therapy. Immunotherapy included low dose (300 mg/m2, maximum 600 mg) pre-treatment cyclophosphamide for regulatory T-cell depletion. erMRI was done at baseline and after 2 months of immunotherapy including multiparametric MRI evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments analyzed immune cell subsets using flow cytometry and intracellular cytokine (ICC) staining for MUC-1 specific responses. Results: 28 pts with high risk prostate cancer were enrolled (n=14/arm). As expected, PSA declined in all pts 2 months after ADT. erMRI after 2 months of treatment suggested greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI indicates increased intratumoral diffusion and has been associated with decreased tumor density. The improvements in ADC were seen when one dominant tumor per patient was evaluated (p=0.17) but were more pronounced when up to 3 lesions were evaluated per pt (n=44 lesions; p=0.031). Compared to baseline, there were trends to increases in CTLA4+ CD8+ T-cells consistent with immune activation and decreases in myeloid derived suppressor cells (MDSCs) in pts receiving immunotherapy+ADT coinciding with the erMRI changes. These immune findings were not seen in the ADT alone group. 3 of 14 pts had MUC1 specific immune response by ICC. 2 of these patients had the greatest changes in ADC noted on erMRI over a 2-year period. Conclusions: Based on assessments by erMRI, pts who received ADT+immunotherapy had greater improvements in ADC than pts receiving ADT alone. Given that ADC improvements are associated with decreased tumor density, this suggests a possible greater anti-tumor effect of the ADT-immunotherapy combination vs. ADT alone. These findings were associated with trends to increased activated CD8+ T-cells and decreased MDSCs in pts receiving immunotherapy+ADT, with 3/14 pts having MUC1 specific immune responses. Further studies are required to confirm the potential to use ADC on erMRI as a potential (bio)marker of anti-tumor effect of immune combinations including ADT. Citation Format: Ravi A. Madan, Baris Turkbey, Lauren M. Lepone, Renee N. Donahue, Italia Grenga, Samuel Samuel Borofsky, Peter A. Pinto, Deborah Citrin, Aradhana Kaushal, Andra Krauze, Sheri McMahon, Myrna Rauchhorst, Anna Couvillon, Martin H. Falk, S Peter Eggleton, Stephen C. Greco, Peter L. Choyke, William L. Dahut, Jeffrey Schlom, James L. Gulley. Neoadjuvant immunotherapy with androgen deprivation therapy (ADT) prior to radiation in prostate cancer: Impact on multiparametric prostate MRI and immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-059. doi:10.1158/1538-7445.AM2017-LB-059

Patients (n = 34) with previously untreated, slowly progressive asymptomatic stage I/II multiple myeloma or with stage II/III multiple myeloma in stable response/plateau phase following conventional anti-tumor therapy were immunized repeatedly with the antigen-specific cancer immunotherapeutic agent tecemotide (L-BLP25). Additionally, patients were randomly allocated to either single or multiple low doses of cyclophosphamide to inhibit regulatory T cells (Treg). Immunization with tecemotide resulted in the induction/augmentation of a mucin 1-specific immune response in 47% of patients. The immune responses appeared to involve a Th1-like cellular immune response involving CD4 and CD8 T cells. The rate of immune responses was similar with single versus multiple dosing of cyclophosphamide and in patients with vs. without pre-existing mucin 1 immunity. On-treatment reductions in the slope of M-protein concentration over time (but not fulfilling clinical criteria for responses with conventional anti-tumor agents) were observed in 45% of evaluable patients, predominantly in those without versus with pre-existing mucin 1 immunity and in patients with early stage disease. No differences were seen in patients receiving single or multiple cyclophosphamide dosing. Treatment with tecemotide was generally well tolerated. Repeated vs. single dosing of cyclophosphamide had no impact on Treg numbers and was stopped after a case of fatal encephalitis that was assessed as possibly study-related. Tecemotide immunotherapy induces mucin 1-specific cellular immune responses in a substantial proportion of patients, with preliminary evidence of changes in the M-protein concentration time curve in a subset of patients.

The goals of the present study were to define the effects of simultaneous cisplatin/tecemotide therapy on tumor development in a human mucin 1 (MUC1) transgenic lung cancer mouse model and to examine the effects of radiotherapy (RTX) on splenocytes, serum cytokines, and immune response to tecemotide. Two hundred twenty-six human MUC1 transgenic C57BL/6 mice were used in five studies designed to assess (i) serum cytokine and immune responses following four weekly 10-μg doses of tecemotide; (ii) the effects of simultaneous administration of cisplatin (2.5 mg/kg × 2 doses/cycle × 4 cycles) and tecemotide (2 cycles × 8 weekly 10-μg doses/cycle) therapy on tumor development, serum cytokines, and immune response; (iii) the dose–response effects of RTX on lymphocyte counts 16 hours following doses of 2 to 8 Gy; (iv) the time course of lymphocyte recovery from 16 hours to 20 days following 8-Gy RTX; and (v) the effects of simultaneous administration of RTX (8 Gy) and tecemotide on the immune response to tecemotide (four weekly 10-μg doses). Serum cytokines were analyzed by multiplex immunoassay, IFNγ immune responses by enzyme-linked immunosorbent spot (ELISpot), and lung tumor foci by lung whole mounts. Simultaneous cisplatin/tecemotide therapy resulted in significant and additive reduction in lung tumor foci compared with control mice, with significantly elevated serum IFNγ levels and specific IFNγ immune responses observed in both tecemotide and tecemotide + cisplatin–treated mice. Finally, neither cisplatin nor radiation interfered with the immune response to tecemotide. Cancer Immunol Res; 2(6); 581–9. ©2014 AACR.

Summary Background Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4–12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m 2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. Findings From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5–29·2) with tecemotide versus 22·3 months (19·6–25·5) with placebo (adjusted HR 0·88, 0·75–1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6–36·8) compared with 20·6 months (17·4–23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64–0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6–23·1] vs 24·6 months [18·8–33·0], respectively; adjusted HR 1·12, 0·87–1·44; p=0·38). Grade 3–4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. Interpretation We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding Merck KGaA (Darmstadt, Germany).

Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent cancer immunoediting has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment.

The results of a recently completed Phase III clinical trial suggest that concurrent chemoradiotherapy followed by tecemotide provides superior benefits to Stage IIIa and IIIb non-small cell lung carcinoma patients as compared with sequential chemoradiotherapy followed by tecemotide. These clinical observations will be dissected in a transgenic model of lung cancer that we have recently established (hMUC1.Tg C57BL/6 mice).

30 Background: Endorectal(er) MRI is an emerging tool in assessing intraprostatic tumors. Immunotherapy development in prostate cancer has been limited due to the lack of intermediate (bio)markers of response. Methods: Untreatedpts with high-risk prostate cancer were randomized in a trial (NCT01496131) of standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25). Pts had erMRI at baseline and after 2 months of ADT+/- biweekly immunotherapy. Low dose (300 mg/m2, maximum 600 mg) cyclophosphamide for regulatory T-cell depletion preceded first immunotherapy. Multiparametric MRI included evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments utilized flow cytometry to evaluate immune cell subsets. This analysis focuses on the 2 month neoadjuvant period of ADT+/-immunotherapy before radiation. Results: 28 pts (n = 14/arm) with high risk prostate cancer (Gleason 8-10, PSA > 20, or stage T3) were enrolled. PSA declined in all pts 2 months after ADT. erMRI findings at 2 months indicated greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI suggests improvements in intratumoral diffusion and has been associated with decreased tumor density. This relative improvement between the groups occurred both per patient (p = 0.16) and per lesion (p = 0.031). Relative to baseline, pts receiving immunotherapy+ADT had increases in CTLA4+ CD8+ T-cells consistent with immune activation (p = 0.0134) and decreases in myeloid derived suppressor cells (MDSCs; p = 0.0353) during the neoadjuvant period corresponding to the erMRI changes. These immune findings were not seen in the ADT alone group. Conclusions: Pts who received immunotherapy+ADT for 2 months had greater improvements in ADC values on erMRI, consistent with decreased tumor density, relative to pts receiving ADT alone. Corresponding increases in activated CD8+ T-cells and decreases in MDSCs were seen in pts receiving vaccine+ADT. These preliminary findings suggest that ADC on MRI may be useful in assessing immunologic impact. Further study is warranted. Clinical trial information: NCT01496131.

3036 Background: Tecemotide is a MUC1 antigen-specific cancer immunotherapy. We report results from a phase I/II study of tecemotide in Japanese patients (pts) with no disease progression (PD) afte...

TPS7608 Background: Tecemotide is an antigen-specific cancer immunotherapy targeting the mucinous glycoprotein MUC1, which is overexpressed and aberrantly glycosylated in a number of cancers includ...

TPS3658 Background: Surgical resection is the only potentially curative treatment for colorectal cancer (CRC) metastases. The five-year survival rate following R0 resection of liver mets is 28-39% ...

Background Tecemotide is a MUC1 antigen-specific therapeutic cancer vaccine. In phase III clinical studies, delivery of tecemotide is preceded by a single low dose of cyclophosphamide (CPA) to inhibit regulatory T cells (Tregs) and enhance the response to the tumor-associated antigen. Here, we investigated effects of CPA on the immune environment and tumor growth in preclinical murine models. Methods The effect of CPA was investigated in tumor-free human MUC1 transgenic mice and anti-tumor responses were evaluated in the mice engrafted with syngeneic colorectal and ovarian cancer cells expressing human MUC1. The mice received either vehicle control, CPA (100 mg/ kg), tecemotide (100 μg) or CPA + tecemotide. The immune cell phenotype and function in the spleen were assessed on Days 1, 3 and 7 post-administration.