A phase II study of talimogene laherparepvec for patients with inoperable locoregional recurrence of breast cancer
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ABSTRACT:
SUBMITTER: Kai M
PROVIDER: S-EPMC8593093 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)].163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type.Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease, >2 mm surgical margins, and received chemotherapy as directed by RS. While an RS > 25 did not predict for a higher rate of LRR, an RS > 24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS > 24 versus 10.7 % (p = 0.04) in those whose RS was ? 24. RS was not associated with LRR in patients who received BCT.Breast cancer patients treated with mastectomy for tumors that have an RS > 24 are at high risk of LRR and may benefit from post-mastectomy radiation.
| S-EPMC4869872 | biostudies-literature
Project description:Purpose National Comprehensive Cancer Network guidelines recommend systemic staging imaging at the time of locoregional breast cancer recurrence. Limited data support this recommendation. We determined the rate of synchronous distant recurrence at the time of locoregional recurrence in high-risk patients and identified clinical factors associated with an increased risk of synchronous metastases. Methods A stage-stratified random sample of 11,046 patients with stage II to III breast cancer in 2006 to 2007 was selected from the National Cancer Database for participation in a Commission on Cancer special study. From medical record abstraction of imaging and recurrence data, we identified patients who experienced locoregional recurrence within 5 years of diagnosis. Synchronous distant metastases (within 30 days of locoregional recurrence) were determined. We used multivariable logistic regression to identify factors associated with synchronous metastases. Results Four percent experienced locoregional recurrence (n = 445). Synchronous distant metastases were identified in 27% (n = 120). Initial presenting stage ( P = .03), locoregional recurrence type ( P = .01), and insurance status ( P = .03) were associated with synchronous distant metastases. The proportion of synchronous metastases was highest for women with lymph node (35%), postmastectomy chest wall (30%), and in-breast (15%) recurrence; 54% received systemic staging imaging within 30 days of a locoregional recurrence. Conclusion These findings support current recommendations for systemic imaging in the setting of locoregional recurrence, particularly for patients with lymph node or chest wall recurrences. Because most patients with isolated locoregional recurrence will be recommended locoregional treatment, early identification of distant metastases through routine systemic imaging may spare them treatments unlikely to extend their survival.
| S-EPMC5877801 | biostudies-literature
Project description:Oncolytic viruses represent a novel drug class in which native or modified viruses mediate tumor regression through selective replication within and lysis of tumor cells as well as induction of systemic antitumor immunity capable of eradicating tumor at distant, uninjected sites. Talimogene laherparepvec (TVEC) is a type I herpes simplex virus genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor to increase tumor-antigen presentation by dendritic cells. It is presently the only oncolytic virus approved by the FDA with an indication for advanced melanoma based upon improved durable response rate in a randomized, phase III trial. Clinical trials are underway in melanoma investigating TVEC as neoadjuvant monotherapy and in combination with checkpoint inhibitors for unresectable disease as well as in an array of other malignancies. It is appropriate to review TVEC's biology mechanism of action, clinical indication and future directions as a prototype of the burgeoning class of oncolytic viruses.
| S-EPMC5893211 | biostudies-literature
Project description:Simple Summary Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is the first oncolytic viral immunotherapy to be approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma. Its direct intratumoral injection aim to trigger local and systemic immunologic responses leading to tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T-cells. Its approval has fueled the interest to study its possible sinergy with other immunotherapeutics in preclinical models as well as in clinical contextes. In fact, it has been shown that intratumoral administration of this immunostimulatory agent successfully synergizes with immune checkpoint inhibitors. The objectives of this review are to resume the current state of the art of T-VEC treatment when used in monotherapy or in combination with immune checkpoint inhibitors, describing the strong rationale of its development, the adverse events of interest and the clinical outcome in selected patient’s populations. Abstract Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.
| S-EPMC8003308 | biostudies-literature
Project description:Cutaneous basal cell carcinoma (BCC) is the most common cancer worldwide. We present a single arm, phase II neoadjuvant trial with the oncolytic virus Talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect basal cell carcinomas. Six cycles of T-VEC were applied intralesionally. The primary endpoint of the study, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks) at the time point of surgery, become resectable with primary wound closure without the need for plastic reconstructive surgery like skin flaps or skin grafts, was already achieved after stage I (9/18 patients; 50.0%), thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Only mild adverse events occurred. The 6-months RFS and OS rates were 100%. T-VEC led to a significant increase of cytotoxic T cells, B cells and myeloid cells, and a decrease of Tregs within the tumor microenvironment. We observed a potent induction of T cell receptor clones of antitumoral and antiviral origin, as well as a strong humoral immune response. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect BCCs (EudraCT Number 2018-002165-19).
2024-09-11 | GSE268728 | GEO
Project description:We previously identified 34 genes of interest (GOI) in 2006 to aid the oncologists to determine whether post-mastectomy radiotherapy (PMRT) is indicated for certain patients with breast cancer. At this time, an independent cohort of 135 patients having DNA microarray study available from the primary tumor tissue samples was chosen. Inclusion criteria were 1) mastectomy as the first treatment, 2) pathology stages I-III, 3) any locoregional recurrence (LRR) and 4) no PMRT. After inter-platform data integration of Affymetrix U95 and U133 Plus 2.0 arrays and quantile normalization, in this paper we used 18 of 34 GOI to divide the mastectomy patients into high and low risk groups. The 5-year rate of freedom from LRR in the high-risk group was 30%. In contrast, in the low-risk group it was 99% (p < 0.0001). Multivariate analysis revealed that the 18-gene classifier independently predicts rates of LRR regardless of nodal status or cancer subtype.
| S-EPMC4816846 | biostudies-other
Project description:AIM:To investigate the impact of biological subtypes in locoregional recurrence in Chinese breast cancer patients receiving postmastectomy radiotherapy (PMRT). METHODS AND MATERIALS:About 583 patients who received postmastectomy radiation between 2010 and 2012 were retrospectively analyzed. According to immunohistochemical staining profile, patients were classified into: Luminal A-like, Luminal B-like, HER2-positive, and triple-negative breast cancer (TNBC). Local and regional recurrence (LRR) cumulative incidences were calculated by competing risks methodology and the power of prognostic factors was examined by Gray's test and the test of Fine and Gray. RESULTS:The median follow-up was 70.9 months. About 34 LRR events occurred. For Luminal A, Luminal B, HER2-positive, and TNBC patients, the 5-year LRR cumulative incidence rates were 1.57%, 4.09%, 10.74%, and 10.28%. Compared with Luminal A, HER2-positive subtype and TNBC had a significant increased risk of LRR (HR was 5.034 and 5.188, respectively). In univariate analysis, predictive factors for higher LRR were HER2-positive subtype (HR = 4.43, P < .05), TNBC (HR = 4.70, P < .05), and pN3 (HR = 5.83, P < .05). In the multivariate model, HER2-positive subtype (HR = 5.034, P < .05), TNBC (HR = 5.188, P < .05), and pN3 (HR = 9.607, P < .01) were independent predictors of LRR. LRR without trastuzumab was similar to that of TNBC (without vs TNBC, 17.88% vs 10.28%, P > .05) in HER2-positive subtype patients, while LRR with trastuzumab was approximate to Luminal A (with vs Luminal A, P > .05). Additionally, endocrine therapy also significantly reduced LRR incidence in the luminal subtype cohort (without vs with therapy, 6.25% vs 2.89%, HR = 0.365, P < .1). CONCLUSIONS:Biological subtype was a prognostic factor of LRR in the PMRT setting among Chinese breast cancer patients.
| S-EPMC7131860 | biostudies-literature
Project description:Talimogene laherparepvec (T-VEC, Imlygic®, Amgen, CA, USA) is an oncolytic herpes simplex type 1 virus used as intralesional therapy for unresectable metastatic melanoma in a cutaneous, subcutaneous or nodal location. Talimogene laherparepvec selectively replicates within and lyses tumor cells while producing granulocyte macrophage colony-stimulating factor, which may promote an immune mediated antitumor response. The US FDA approved T-VEC in late 2015 following Phase I-III trials that demonstrated safety and efficacy. Future directions for T-VEC include combination therapies with other systemic immunotherapies such as anti-CTLA-4 antibody and anti-PD-1 drugs. Current National Comprehensive Cancer Network (NCCN) practice guidelines have added T-VEC as a primary treatment for stage IIIB/C and stage IVM1a melanoma patients.
| S-EPMC6094674 | biostudies-literature
Project description:BackgroundSoft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma.MethodsWe explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS >5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed.ResultsNo dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone.ConclusionPreoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies.Trial registration numberNCT02453191.
| S-EPMC8327848 | biostudies-literature
Project description:Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response. In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8+ T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response. Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8+ T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8+ T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8+ T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8+ T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions. This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy. NCT02366195.
| S-EPMC8011715 | biostudies-literature