Clinical Objective Response Rate Research Articles

α-d-Glucose-1,6-Biphosphate Induces Dendritic Cell Homing to Enhance the Antitumor Effect of Neoantigen Vaccines.

Neoantigen vaccines have achieved good therapeutic effects in animal experiments and early clinical trials on certain malignant tumors. However, their overall objective effectiveness in clinical trials still needs to be improved. Low-efficiency dendritic cell (DC) migration (<5%) to lymph nodes is one of the factors that limits vaccine effectiveness. For neoantigen vaccines, improving the homing efficiency of DCs is expected to further improve the immunotherapeutic effect. In this study, we used α-d-glucose-1,6-biphosphate (α-d-Glu), a metabolite that successfully enhanced C57BL/6J mouse bone marrow-derived DC homing induced by neoantigen peptide, mRNA, and DC vaccines during the administration process and improved the antitumor effects in the mouse C57BL/6J model with a neoantigen vaccine. We clarified that α-d-Glu activated MAPK8IP1 by inhibiting the expression of microRNA-10a-5p, thereby activating the MAPK signaling pathway to promote DC homing. Excitingly, the efficiency of α-d-Glu in promoting DC migration is not weaker than that of PGE2, which is the gold standard used to promote DC migration in clinical trials of DC vaccines. Thus, this study lays the foundation for further enhancing the objective clinical response rate of neoantigen vaccines and overcoming the limitation of an insufficient clinical response rate for neoantigen vaccines caused by low DC homing efficiency.

Nanomedicine sheds new light on cancer immunotherapy.

Cancer immunotherapy comprising of immune checkpoint blockade (ICB) therapy, immune cell therapies, cancer vaccines and many others represents a profound arsenal in the fight against different types of cancers. However, their overall clinical objective response rates, particularly against most solid tumors, are still not sufficient owing to a variety of reasons including the heterogenous expression of tumor antigens, limited tumor infiltration of effector immune cells, acquired tumor immunosuppression and some other factors. In recent years, various nanomedicine strategies have been proposed to assist cancer immunotherapy via distinct mechanisms, presenting new promises in many published studies. This perspective willthus provide a brief overview regarding the development of nanomedicine platforms for improving cancer immunotherapy.

Efficacy and Satisfaction of Low Doses UVA1 Phototherapy: A Spanish Experience from a Single Centre.

UVA1 phototherapy is a treatment used for multiple dermatological conditions. The optimal therapeutic regimens and dosing of UVA1 are a matter of debate. The dosages used vary widely between published studies and there are no evidence-based protocols that provide data on dosage, duration, or the role of maintenance therapy. The purpose of this study is to evaluate the experience in our medical center regarding treatment with UVA1, as well as the degree of patient satisfaction with the treatment according to their pathology. We present a retrospective evaluation of outcomes, treatment tolerability, and satisfaction in adult patients using a low dose of UVA1 phototherapy, administered in our dermatologic service between 2019 and 2022. A total of 78 patients were treated with UVA1, of whom 46 patients (59%) were over 18 years old, completed treatment, and gave their consent. The overall objective clinical response rate was 91.30% (42/46), achieving a complete response in 17 (36.96%) patients, partial response in 25 (54.34%), and no response in 4 (8.70%). The complete response rates recorded were high in morphea, scleredema, or chronic hand eczema. In terms of the level of satisfaction objectively measured by TSQM-9 version 1.4, highlighting high scores obtained in mastocytosis, systemic sclerosis, morphea, scleredema, chronic hand eczema, or prurigo nodularis (over 65 points). We present a review of treatment with UVA1 phototherapy at low doses with good response in a wide variety of dermatological pathologies.

Efficacy and safety of tislelizumab plus cetuximab and irinotecan in patients with previously treated RAS wild-type advanced colorectal cancer: A phase II, single-arm study.

125 Background: For adequately treated patients (pts) with advanced colorectal cancer, the current third-line treatment standard of TKIs or TAS-102 administration has a low clinical objective response rate and its effectiveness seems to be limited. Preclinical studies have suggested that EGFR pathway blockage and immune checkpoint inhibition have synergistic therapeutic effects in these pts. The purpose of this study was to examine the efficacy and safety of tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan in pts with previously treated RAS wild-type advanced colorectal cancer. Methods: This is an open-label, single-arm, phase II study. RAS wild-type advanced colorectal cancer pts with at least two previous lines of therapy were included in this study and administered with tislelizumab plus cetuximab and irinotecan until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) (RESCIT 1.1). Secondary endpoints included DCR, PFS, OS and safety. Results: In total, 35 eligible RAS wild-type advanced colorectal cancer pts were enrolled from March 2021 to September 2021. The median age was 58 years. All 35 pts were identified as BRAF/RAS wild-type, and 33 (94%) had left-sided colon cancer. The percentages of pts with second-line, third-line and ≥fourth-line previous treatments were 37%, 49%, and 14%, respectively. Thirty-four pts (97%) had received targeted therapies previously, including 29 (83%) with anti-EGFR therapy. By Aug 17th, 2022, 2 pts had withdrawn from the study for personal reasons, and the remaining 33 pts were evaluated for efficacy. Twelve of the 33 (36.4%) pts achieved clinical partial remission and 14 (42.4%) achieved stable disease; disease progression occurred in 6 pts and 1 patient died. The unconfirmed ORR was 36.4% and the DCR was 78.8%. The confirmed ORR was 33.3%. Until Aug 17th, 2022, 1 pts continued treatments. The median PFS was 6.83 months. Among the 33 treated pts, 32 (97.0%) had treatment-related adverse events (AEs). Common AEs included rash (n=32), fatigue (n=30), decreased appetite (n=30), nausea (n=28), diarrhea (n=16), vomiting (n=14), liver dysfunction (n=13), leukopenia (n=12) anemia(n=10), neutropenia (n=9), paronychia (n=8), oral mucositis (n=4), and thrombocytopenia (n=4). Three (9.1%) of the 33 pts reported grade ≥3 AEs, including rash (n=1), neutropenia (n=2). Conclusions: Tislelizumab plus cetuximab and irinotecan showed an encouraging clinical efficacy and tolerable safety in previously treated pts with RAS wild-type advanced colorectal cancer. Clinical trial information: NCT05143099 .

Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer

Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects. To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase. This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III. Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks. The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes. A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase. In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted. ClinicalTrials.gov Identifier: NCT03881878.

Efficacy and safety of tislelizumab plus cetuximab and irinotecan in patients with previously treated RAS wild-type advanced colorectal cancer: Preliminary findings of a phase II, single-arm study.

3566 Background: For adequately treated patients (pts) with advanced colorectal cancer, the current third-line treatment standard of TKIs or TAS-102 administration has a low clinical objective response rate and its effectiveness seems to be limited. Preclinical studies have suggested that EGFR pathway blockage and immune checkpoint inhibition have synergistic therapeutic effects in these pts. The purpose of this study was to examine the efficacy and safety of tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan in pts with previously treated RAS wild-type advanced colorectal cancer. Methods: This is an open-label, single-arm, phase II study. RAS wild-type advanced colorectal cancer pts with at least two previous lines of therapy were included in this study and administered with tislelizumab plus cetuximab and irinotecan until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) (RESCIT 1.1). Secondary endpoints included DCR, PFS, OS and safety. Results: In total, 35 eligible RAS wild-type advanced colorectal cancer pts were enrolled from March 2021 to September 2021. The median age was 58 years. All 35 pts were identified as BRAF/RAS wild-type, and 33 (94%) had left-sided colon cancer. The percentages of pts with second-line, third-line and ≥fourth-line previous treatments were 37%, 49%, and 14%, respectively. Thirty-four pts (97%) had received targeted therapies previously, including 29 (83%) with anti-EGFR therapy. By December 31, 2021, 2 pts had withdrawn from the study for personal reasons, and the remaining 33 were evaluated for efficacy. Twelve of the 33 (36.4%) pts achieved clinical partial remission and 14 (42.4%) achieved stable disease; disease progression occurred in 6 pts and 1 patient died. The ORR was 36.4% and the DCR was 78.8%. Until December 31, 2021, 23 pts continued treatments, and the median PFS was not reached. Among the 33 treated pts, 32 (97.0%) had treatment-related adverse events (AEs). Common AEs included rash (n = 32), fatigue (n = 29), decreased appetite (n = 24), nausea (n = 24), diarrhea (n = 13), liver dysfunction (n = 10), vomiting (n = 7), leukopenia (n = 7), anemia (n = 6), paronychia (n = 5), oral mucositis (n = 4), and neutropenia (n = 4). Four (12%) of the 33 pts reported grade ≥3 AEs, including rash (n = 1), neutropenia (n = 2) and vomiting (n = 1). Conclusions: Tislelizumab plus cetuximab and irinotecan shows an encouraging clinical efficacy and tolerable safety in previously treated pts with RAS wide-type advanced colorectal cancer. Clinical trial information: NCT05143099.

Vismodegib for treatment of periocular basal cell carcinoma – 6-year experience from a tertiary cancer center

BackgroundThe treatment of advanced periocular basal cell carcinomas becomes a challenge as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog inhibitor approved for the treatment of locally advanced tumors or metastatic disease. ObjectiveAnalyze the results of treatment with vismodegib for advanced periocular basal cell carcinomas in a real-life setting of a reference center between 2014 and 2020. MethodsRetrospective longitudinal study. The patient's demographic profile, comorbidities, tumor characteristics, and treatment outcomes were analyzed. ResultsA total of 13 patients were included. Median follow-up and treatment duration were 15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had a complete response and 46.2% a partial response. The median duration of response was 13 months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after the beginning of treatment. Eighty-four percent of the patients had at least one adverse event, and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability. Study limitationsBeing a retrospective study in a real-life setting, the evaluation of objective clinical response was subjective to physician appreciation. ConclusionVismodegib is a safe and effective treatment for locally advanced basal cell carcinoma. To prevent recurrences, the drug should be used continually when tolerated. The role of neoadjuvant vismodegib before surgery is being investigated and might add an important step in searching for a definitive treatment for these cases.

Abstract IA17: Molecular mechanisms of T-cell exhaustion and implications for immunotherapy

Abstract T-cell exhaustion is common during chronic infections and cancer and prevents optimal immunity. Exhausted CD8 T cells (TEX) are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. TEX also co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at reinvigorating TEX. Despite the clinical success of PD-1-based therapies in human melanoma and other cancers, the majority of patients do not have durable clinical benefit from anti-PD-1 monotherapy. A major challenge remains identifying which patients will respond to anti-PD-1 therapy and defining the underlying mechanisms for successful, durable response versus treatment failure. Detailed immune profiling of peripheral blood from stage IV melanoma patients before and after pembrolizumab (pembro) identified reinvigoration in circulating TEX. These data indicated that nearly 80% of patients experienced a strong, on-target immunologic effect of PD-1 blockade. However, the objective clinical response rate in this cohort was less than 40% and reinvigoration of circulating TEX alone did not predict clinical outcomes. We are currently now using neoadjuvant clinical trial designs and preclinical models to dissect the molecular and mechanistic features of effective and ineffective responses to checkpoint blockade and to understand the underlying molecular program of exhausted CD8 T cells. Our emerging data not only provide a framework for dissecting distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic treatment approaches, but also point to key underlying molecular pathways involved in programming and controlling the developmental biology of exhausted T cells. The implications of these findings for clinical therapies will be discussed. Citation Format: E. John Wherry. Molecular mechanisms of T-cell exhaustion and implications for immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA17.

183PD - Neoadjuvant endocrine therapy with palbociclib in patients with high-risk breast cancer

BackgroundOptimal neoadjuvant therapy for luminal A breast cancer remains a topic of controversy. MethodsIn the phase 2 PETREMAC trial (NCT02624973), patients with large T2 (>4cm) or locally advanced breast cancers and luminal A characteristics (ER>50%, HER2- and TP53WT) received neoadjuvant endocrine therapy (NET) and CDK4/6 inhibition in concert. NET consisted of letrozole (postmenopausals) or tamoxifen + goserelin (premenopausals). Palbociclib (P) was added if Ki67 had decreased <50% after 14 days on NET. Neoadjuvant chemotherapy (NAC: docetaxel) was introduced if NET + P decreased Ki67 <50% or if NET +/- P did not cause an objective response (OR). Pre-treatment tumor biopsies underwent targeted DNA sequencing of 360 cancer-related genes. Results88 patients were enrolled; mean tumor diameter 55mm (range 20-95). 2 patients lacked Ki67 data for analysis, 1 was a screening failure. 47/85 (55%) had a drop >50% on NET alone. Among the remaining 38 patients, 31 had P added in concert, 5 had Ki67<10% before NET and did not receive P, 2 had missing data. NET + P yielded a Ki67drop >50% in 22/31 patients (71%). NAC was required in 28/84 patients (33%) after NET +/- P. Thus far, 84 patients have completed neoadjuvant treatment, and 75 have surgery results ready. The clinical OR rate (ORR) before surgery was 24/32 for NET alone, 12/15 for NET + P and 24/28 for NAC after NET +/- P. The overall ORR before surgery was 85% (60/75, 13 w/missing data), and ORR 77% (36/47) for NET +/- P. Pathological complete response (pCR) has been observed in 4/75 patients at surgery, where 3/4 with pCR received NAC after NET +/- P. 40/88 tumors (45%) had mutations in the PI3K pathway; PIK3CA (33%), PTEN (6.8%) and AKT1 (4.5%). 5/15 lobular carcinomas (33%) and 16/73 other carcinomas (22%) harbored CDH1 mutations. CDH1 mutations were associated with a higher probability of Ki67 reduction >50% on NET alone (CDH1 mutated: 15/20 vs CDH1WT: 32/66; p=0.042). ConclusionsNET +/- P was effective at reducing cell proliferation and yielded an ORR of 77% in these ER+, HER2 negative breast cancers. NAC was required only among 33% of the patients. CDH1 mutations seem predictive of response to NET in this setting. Clinical trial identificationNCT02624973; 2015-002816-34. Legal entity responsible for the studyHaukeland University Hospital, Bergen, Norway. FundingDet Regionale Samarbeidsorganet/Helse Vest, Pfizer. DisclosureP.E. Lønning: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self): Roche; Advisory / Consultancy: Laboratorios Farmaceuticos Rovi; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Licensing / Royalties: Cytovation. E.S. Blix: Honoraria (self): Pfizer. B. Gilje: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Astellas Oncology; Research grant / Funding (institution): Cellgene; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Pierre Fabre. E.A. Janssen: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. J. Geisler: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Speaker Bureau / Expert testimony: Brystol-Myers-Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer. T. Aas: Honoraria (self): AstraZenaca; Honoraria (self): Roche. S. Knappskog: Honoraria (self), Research grant / Funding (institution): AstraZenaca; Honoraria (self), Research grant / Funding (institution): Pfizer; Licensing / Royalties: Patent EP2389450 A1,Patent WO 2012/010661. H.P. Eikesdal: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZenaca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): HAI Interaktiv AS; Honoraria (self): Dagens Medisin; Honoraria (self): Brystol-Myers-Squibb; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Abbvie. All other authors have declared no conflicts of interest.

Abstract P4-06-10: Immune related gene expression to explore immue escape in primary to metastatic breast cancer transition

Abstract Background: Targeting programmed cell death receptor l pathway (anti-PD-1/PD-L1) demonstrated objective clinical response rates in a subgroup of patients with metastatic breast cancer with overall response rates of up to 20%. However, the vast majority of breast cancer patients is not responding to immune checkpoint blockade. With regard to the diverse tumor biology of breast cancer and recent data, immune evasion is likely mediated by various, coincident mechanisms. Consequently, our objective was to identify patterns of immune responses during the transition of primary to metastatic breast cancer. Methods: We performed comprehensive immunohistochemistry on both tumor and immune cells in two independent, matched cohorts of 67 primary and metastatic breast cancer patients. Further, the analysis was integrated with mRNA expression levels (RT-qPCR) of key regulatory and effector function immune genes and clinical as well as histopathologic parameters. Results: Both, immunohistochemistry and mRNA gene expression profiling of immune genes revealed immunological ignorance, defined as an immunological “cold” tumor by particularly low infiltration of CD8+ T cells and corresponding immune gene and effector function, as a key feature of primary to metastatic breast cancer transition. However, CD8+ T cell infiltration and effector function (Granzyme B, Interferon-γ) where found to be an independent prognostic marker for PFS and OS. Unsupervised hierarchical clustering and regression analysis identified distinct immune response types according to T-cell infiltration, interferon-γ signalling (IFNG), immunosuppression (IDO, TGF-β, FOXP3) and humoral immune responses (Immunoglobulin κ constant; IGKC). Expression of programmed death receptor 1 ligand (PD-L1), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) where linked to CD8+ T cells and associated with a better prognosis only in triple negative breast cancer patients. Importantly, induction of CD4+ and CD8+ T cell infiltration as well as humoral immune responses (IGKC, CXCL13) in matched pairs during progression from primary to metastatic disease, where strongly associated with improved distant disease free and overall survival. Conclusion: Our findings demonstrate a switch to a less immunoreactive environment in metastatic compared to matched, primary samples of breast cancer patients. Nevertheless, induction of T-cell mediated immunity during tumor evolution, observed across all biologic subtypes, warrants further research with the overall goal to convert immunologically ignorant breast cancers and to stratify future immunotherapies. Citation Format: Fremd C, Halama N, Wirtz R, Zoernig I, Sinn H-P, Varga Z, Feisst M, Deutsch T, Schuetz F, Schneeweiss A, Jaeger D, Wallwiener M. Immune related gene expression to explore immue escape in primary to metastatic breast cancer transition [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-10.

Safety and efficacy of decitabine-primed anti-PD-1 (SHR-1210) treatment in patients with relapsed/refractory classical Hodgkin lymphoma.

7537Background: More than 50% unprecedented objective clinical response rate led to a rapid approval of anti-PD-1 antibodies by FDA using in patients with relapsed/refractory classical Hodgkin lymp...

Abstract OT1-02-01: Phase II neoadjuvant trial of nanoparticle almumin-bound paclitaxel and trastuzumab in patients with node-negative, Her-2 positive breast cancer (OMC-BC04)

Abstract Background: Neoadjuvant chemotherapy plus trastuzumab results in a 30% to 50% pathologic complete response (pCR) rate in HER-2 positive breast cancer and has been associated with improved therapeutic outcomes. Thus, the pCR rate can be useful in evaluating novel agents in this patient population. Albumin-bound (nab)-paclitaxel can reduce the toxicity of Paclitaxel while maintaining its efficacy. We reported that neoadjuvant therapy using Anthracycline based regimens (EC,AC,FEC) followed by a combination with nab-Paclitaxel and Trastuzumab was effective and safe by OMC-BC01 Study (Tanaka et al. Clin Breast Cancer 15:191-196). The pCR rate was 36% and 71% in the patients with estrogen receptor-positive and negative cancer, respectively. In addition, Tolaney et al. showed that adjuvant Paclitaxel and Trastuzumab for node-negative, HER-2 positive tumors measuring up to 3 cm in greatest dimension was associated with patients outcomes that were better than expected on the basis of historical data (Tolaney et al. N Engl J MED.2015 Jan 8:372(2):134-141). We conducted a clinical Phase II, multicenter, neoadjuvant trial of combination with nanoparticle albumin-bound Paclitaxel and Trastuzumab in patients with node-negative, Her-2 positive, estrogen receptor-negative breast cancer measuring up to 3 cm in greatest dimension. Patients and Methods: nab-Paclitaxel and Trastuzumab as neoadjuvant therapy in patients with Her-2 positive, node-negative, estrogen receptor-negative breast cancer measuring up to 3 cm in greatest dimension. Patients are treated with neoadjuvant nab-Paclitaxel (260mg/m2) and Trastuzumab q21d x 4, and undergo surgery 4-6 weeks later from completing chemotherapy. The primary endpoint, pCR is defined as no evidence of invasive tumors in the final surgical sample both in the breast and axillary lymph nodes. Secondary endpoints include objective clinical response rate, histological response rate, disease-free interval, rate of breast conserving surgery, and the safety of the treatment. Accrual: Presently, a total number of 1 patient have been included since start of the study. The expected end of accrual of 30 patients will be the last quarter 2018. Citation Format: Iwamoto M, Tanaka S, Koda C, Kawaguchi K, Terasawa R, Sato N, Fujioka H, Kimura K, Uchiyama K. Phase II neoadjuvant trial of nanoparticle almumin-bound paclitaxel and trastuzumab in patients with node-negative, Her-2 positive breast cancer (OMC-BC04) [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 OT1-02-01.

Abstract PR05: Peripheral blood immune profiling of anti-PD-1 therapy in human melanoma reveals a link between T cell re-invigoration and tumor burden that predicts response

Abstract Despite the clinical success of PD-1 based therapies in human melanoma patients, the majority of patients do not have durable clinical benefit from anti-PD-1 monotherapy. A major challenge remains identifying which patients will respond to anti-PD-1 therapy and defining the underlying reasons for successful response versus treatment failure. Pre-existing T cell infiltration and/or PD-L1 expression in tumors may predict clinical responses; however, the use of blood-based profiling to understand the immunologic mechanism of PD-1 blockade has been less explored. Here we used detailed immune profiling of peripheral blood from stage IV melanoma patients before and after pembrolizumab (pembro), and identified pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (TEX). Robust induction of Ki67 in this subset of circulating CD8 T cells post-therapy (re-invigoration) occurred in 78% of patients indicating strong, on target immunological effects of PD-1 blockade in most patients studied here. Despite this high immunological response rate, the objective clinical response rate in this cohort was less than 40%. Ki67 in CD8 T cells alone did not predict clinical outcomes and, in fact, higher systemic immune activation at baseline was associated with lower overall survival. Rather, the magnitude of re-invigoration of circulating TEX in relation to pre-treatment tumor burden correlated with clinical response. We identified a TEX re-invigoration to tumor burden ratio which could be used to predict clinical response and overall survival as early as 6 weeks post therapy. Consistent observations were found in a second independent cohort and suggest that clinical failure of PD-1 blockade in many patients may not solely be due to an inability to induce immune re-invigoration but rather, an imbalance between T cell re-invigoration and tumor burden. Thus, by focused profiling of a mechanistically relevant circulating T cell subpopulation calibrated to pre-treatment disease burden, we identify a clinically accessible predictor of response to PD-1 blockade. These findings also provide a framework for dissecting distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic treatment approaches. Citation Format: Alexander Huang, Michael A. Postow, Robert J. Orlowski, Rosemarie Mick, Bertram Bengsch, Sasi Manne, Wei Xu, Shannon Harmon, Matthew Adamow, Deborah Kuk, Katherine Panangeas, Cristina Carerra, Phillip Wong, Felix Quagliarello, Kristen E. Pauken, Ramin S. Herati, Suzanne McGettigan, Shawn Kothari, Sangeeth M. George, Brandon Wenz, Kurt D'Andrea, Xiaowei Xu, Ravi K. Amaravadi, Giorgos Karakousis, Lynn M. Schuchter, Katherine L. Nathanson, Jedd D. Wolchok, Tara C. Gangadhar, John Wherry. Peripheral blood immune profiling of anti-PD-1 therapy in human melanoma reveals a link between T cell re-invigoration and tumor burden that predicts response [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR05.

Peptide vaccination therapy: Towards the next generation.

The aim of peptide vaccination therapy is to stimulate and activate peptide-specific T cells to reject tumor cells. This strategy has been promoted by the discovery of tumor-associated antigens recognized by T cells. Peptide vaccination therapy can induce immune responses in some cancer patients but the objective clinical response rates are still low. To improve of the efficacy of peptide vaccination therapy: (i) cancer stem cell antigens specifically expressed in carcinoma/sarcoma stem-like cells but not in normal cells are needed; (ii) peptide vaccination therapy should be performed in the earlier stages; and (iii) memory T stem cells should be regulated to maintain long-lasting immune responses to the peptide vaccination.

Antigen-specific TIL therapy for melanoma: A flexible platform for personalized cancer immunotherapy.

Tumor infiltrating lymphocyte (TIL) therapy has shown objective clinical response rates of 50% in stage IV melanoma patients in a number of clinical trials. Nevertheless, the majority of patients progress either directly upon therapy or after an initial period of tumor control. Recent data have shown that most TIL products that are used for therapy contain only low frequencies of T cells reactive against known melanoma-associated epitopes. Because of this, the development of a technology to create T-cell products that are enriched for reactivity against defined melanoma-associated antigens would seem valuable, both to evaluate the tumoricidal potential of T cells directed against different antigen classes and to potentially increase response rates. Here, we developed and validated a conditional MHC streptamer-based platform for the creation of TIL products with defined antigen reactivities. We have used this platform to successfully enrich both high-frequency (≥1%) and low-frequency (<1%) tumor-specific CD8(+) T-cell populations, and thereby created T-cell products with enhanced tumor recognition potential. Collectively, these data demonstrate that selection of antigen-specific T-cell populations can be used to create defined T-cell products for clinical use. This strategy thus forms a highly flexible platform for the development of antigen-specific cell products for personalized cancer immunotherapy.

Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients.

PurposeWe aimed to determine the rate of pathological complete response (pCR), clinicopathological factors associated with pCR, and clinical outcomes following neoadjuvant chemotherapy in locally advanced breast cancer.MethodsMedical records of patients who had undergone neoadjuvant chemotherapy for breast cancer between January 2007 and September 2011 were retrospectively reviewed, and the pCR rates were calculated according to three sets of criteria: the National Surgical Adjuvant Breast and Bowel Project (NSABP), the MD Anderson Cancer Center (MDACC), and the German Breast Group (GBG). Tumors were classified as luminal A like, luminal B like, human epidermal growth factor receptor 2 (HER2), or triple-negative. pCR and clinical outcome, including overall survival (OS) and disease-free survival (DFS) rates were analyzed at the median follow-up of 54.2 months.ResultsOf a total of 179 patients who had received neoadjuvant chemotherapy, 167 patients (93.3%) had locally advanced breast cancer and 12 patients (6.7%) had early-stage breast cancer. The majority of patients (152 patients, 89.4%) received anthracycline-based neoadjuvant chemotherapy. The objective clinical response rate was 61.5%, comprising clinical partial response in 5.5% and clinical complete response in 3.9% of patients. Twenty-one (11.7%), 20 (11.2%), and 17 patients (9.5%) achieved pCR according to NSABP, MDACC, and GBG definitions, respectively. pCR rates, as defined by NSABP, according to breast cancer subtype were 4.4%, 9.7%, 24.2%, and 19.2% in luminal A like, luminal B like, HER2, and triple-negative subtypes, respectively. Patients who achieved pCR had significantly better DFS (5-year DFS rates, 80% vs. 53%, p=0.030) and OS (5-year OS rates, 86% vs. 54%, p=0.042) than those who did not.ConclusionThe pCR rate following neoadjuvant chemotherapy for breast cancer in Thai women attending our institution was 11.7%; pCR was more frequently observed in HER2 and triple-negative breast tumor subtypes. Patients who achieved pCR had significantly improved survival.

Abstract C295: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Abstract Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50&amp;lt;1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. PARP inhibition has also been shown to be effective in preclinical models of small cell lung cancer and Ewing sarcoma, possibly related to high PARP expression. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES). Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 µg/d with 1000 µg/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC's was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively. Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet. Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway. Clinicaltrial.gov ID: NCT01286987 BRCA Breast and Ovarian CancerNBRCA Tumor TypeResponse18BreastCRPRSD &amp;gt; 12 weeksCBR*18Breast1 (6%)9 (50%)∧14 (78%)Response - 25 RECIST evaluable; 27 CA-125 evaluable28Ovarian28OvarianCRPRCA-1251 (4%)10 (40%)19 (70%)2PancreasCRPRSD ≥ 12 weeks2Pancreas0 (0%)0 (0%)2 (100%)**∧3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C295. Citation Format: Zev A. Wainberg, Johann S. de Bono, Lida Mina, Jasgit Sachdev, Lauren Averett Byers, Rashmi Chugh, Charlie Zhang, Joshua W. Henshaw, Andrew Dorr, John Glaspy, Ramesh Ramanathan. Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C295.

P3-14-25: Neoadjuvant Trastuzumab and Paclitaxel Combination Induces a High Rate of Pathological Complete Responses in Locally Advanced Breast Cancer by Exploiting Host Antitumor Immunity.

Abstract Background: A phase II study was performed to assess the role of patients’ immune profile in the activity of a trastuzumab-based, non anthracycline containing neoadjuvant chemotherapy (NC) regimen in locally advanced breast cancer (BC) patients (pts). Methods: Newly diagnosed T2-3 HER2+ BC pts received a 12 week NC with weekly paclitaxel and trastuzumab, which was continued for further 12 weeks before surgery in the absence of progression (PRO). Further 12 weeks of the same therapy was planned after surgery and then trastuzumab alone to 1 year of treatment ± hormonal therapy and radiotherapy. In case of PRO, trastuzumab was discontinued and anthracyclines were planned. Blood samples were collected at diagnosis and every 3 months for 1 year then yearly. The % of NK cells, T cells and Treg cells was evaluated by flow cytometry, and serum levels of 9 cytokines were assessed by SearchLight multiplex array technology. Circulating CD8+ T cells specific for a broad spectrum of tumor-associated antigens (Her2, muc-1, mammaglobin-A, trag-3, survivin, bcl-xL) were enumerated by IFN-γ Elispot and in vitro T-mediated, antibody-dependent cell cytotoxicity (ADCC) was assessed using patients’ PBMCs. Results: From July 2006, 34 pts were enrolled, median age 46 yrs (range 30–70). Overall objective clinical response rate was 91%, with 53% of pathological complete responses (pCR) and 38% of partial responses. At a median follow-up of 27 months, 4 relapses were noted (1 brain, 1 local breast, 2 bone). No cardiotoxicity occurred. At diagnosis, pts showed an immune profile similar to that of healthy women, whereas higher numbers of Treg cells (p=0.02), NK cells (p=0.03), lower T cell numbers (p&amp;lt;0.01) and lower amounts of serum IL-2, IL-6, and IL-8 were found in a concomitant control group of untreated HER2− pts. Moreover, spontaneous CD8+ T cells specific for all 13 HLA-A*0201 epitopes were observed in the whole series, with numbers usually higher than those observed in HER2− cases. Notably, patients with pCR, unlike those showing partial responses, retained high numbers of epitope-specific CD8+ T cells throughout the NC treatment, particularly versus survivin and mammaglobin-A epitopes. Moreover, pts achieving pCR showed at diagnosis a significantly higher efficiency of trastuzumab-mediated ADCC compared to pts with partial responses (p=0.05). The treatment also induced a progressive increase in the number of NK cells and in the efficiency of trastuzumab-mediated ADCC. Conclusions: NC with paclitaxel and trastuzumab induces high rates of pCR with no cardiotoxicity. This clinical efficacy is favoured by the retained immunological proficiency of HER2+ pts, who may benefit from the immunological synergism between the two drugs. In fact, the increased number and activation of NK cells promoted by paclitaxel likely favour NK-dependent ADCC responses, known as one of trastuzumab's main mechanisms of action. The possible role of trastuzumab-mediated ADCC in preserving event-free survival and the involvement of paclitaxel in inducing NK cells’ NF-kB nuclear translocation are under evaluation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-25.

OT1-02-01: Phase II Neoadjuvant Trial of Anthracycline Based Regimens Followed by a Combination with Nanoparticle Almumin-Bound Paclitaxel and Trastuzumab in Patients with Operable T2-3,N0-1,Her2 Positive Breast Cancer.

Abstract Background: Anthracycline and taxane have been widely used and studied in neoadjuvant setting for treatment of locally advanced breast cancer. Various regimens have explored the addition of newer agents to determine safety and efficacy, and pathological complete response(pCR) has been demonstrated to be associated with favorable overall survival in primary breast cancer. In addition, Three year median follow-up data of the TECHNO Trial revealed that the neoadjuvant combination of trastuzumab and chemotherapy resulted in a high chance for a pCR. We conducted a clinical Phase II neoadjuvant trial of Anthracycline based regimens(EC,AC,FEC) followed by a combination with nanoparticle albumin-bound Paclitaxel and Trastuzumab in patients with operable T2-3,N0-1,Her2 positive breast cancer. Patients and Methods: The study is designed to evaluate EC or AC or FEC followed a combination of nanoparticle almumin-bound Paclitaxel and Trastuzumab as neoadjuvant therapy in patients with Her2 positive locally advanced(T2-3,N0-1) breast cancer. Patients are treated with neoadjuvant EC(Epirubicin 90 mg/m2, Cyclophosphamide 600 mg/m2) or AC(Doxorubicin 90 mg/m2, Cyclophosphamide 600 mg/m2) or FEC(Fluorouracil 500mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) q21d x 4, follosed by a combination with nanoparticle almumin-bound Paclitaxel(260 mg/m2) and Trastuzumab q21d x 4. Patients undergo surgery 4–6 weeks later from completing chemotherapy. pCR, the primary endpoint is defined as no evidence of invasive tumors in the final surgical sample both in the breast and axillary lymph nodes. Secondary endpoints include objective clinical response rate, disease-free interval, overall survival, rate of breast concerving surgery, and the safety of the treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-01.

A study of the recurrence score by the 21-gene signature assay as a predictor of clinical response to neoadjuvant exemestane for 24 weeks in estrogen-receptor-positive breast cancer.

558 Background: Exemestane (EXE) is a steroidal aromatase inhibitor, one of the key drugs for postmenopausal ER-positive breast cancer patients (pts). We have reported that 24 wks neoadjuvant treatment of EXE has shown attractive response with sufficient safety and tolerability from multicenter phase II trial (JFMC34-0601; Toi M, et al. Cancer Science, 2011). The additional translational investigations were performed to find biomarkers that might be recommended for individualizing treatment in the neoadjuvant setting. This exploratory study was conducted to investigate the clinical usefulness of the 21-gene signature (OncotypeDX) for prediction of response to neo-EXE therapy. Methods: We tested whether the Recurrence Score (RS) by the 21-gene signature determined on core biopsy specimen at baseline would correlate with clinical objective response rate (ORR) in pts who were enrolled in the JFMC34-0601 trial. Postmenopausal pts over 55-yrs-old were eligible with confirmed Stage II or IIIA invasive breast cancer and ER-positive status. Results: Of 116 pts registered between 2006 and 2008, RS was obtained for 64 pts with adequate sufficient tissue. The median age and tumor size were 64 yrs (range, 56-77) and 27 mm (15-58). There were 47/15/2 pts for stage IIA/IIB/III and 2/50/12 pts for HER2-positive/negative/equivocal. The numbers of pts in the low, intermediate, or high RS groups were 32 (50%), 17 (27%), and 15 (23%), respectively. ORR to neo-EXE therapy was 59% (95%CI, 40–76%), 59% (33–82%), and 20% (4–48%) for pts in the low, intermediate, and high RS groups, respectively. There was a significant difference for ORR between the low and the high RS groups (P=0.015, Fisher exact test). In a multivariate logistic regression model, the continuous RS provided significant predictive power that was independent of age and tumor size (P=0.019, likelihood ratio test). Conclusions: This is the first report that the 21-gene signature has value in predicting a response to neo-EXE therapy in postmenopausal pts with ER-positive breast cancer, and provides preliminary evidence for the clinical usefulness of the neoadjuvant treatment selection.