Papers by Anita Giobbie-hurder
Cancer immunology research, Jun 1, 2017
The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (... more The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking antiangiogenesis and immune checkpoint blockade. Cancer Immunol Res; 5(6); 446-54. Ó2017 AACR.
Journal for ImmunoTherapy of Cancer, Nov 1, 2021
Background Angiogenic factors promote the growth of tumor vasculature, modulate lymphocyte traffi... more Background Angiogenic factors promote the growth of tumor vasculature, modulate lymphocyte trafficking into tumors, and inhibit maturation of dendritic cells. We hypothesized that MEDI3617, a human IgG1 kappa monoclonal antibody directed against human angiopoietin-2, in combination with tremelimumab (treme), an IgG2 monoclonal antibody blocking cytotoxic T-lymphocyte-associated protein-(CTLA-4), is safe in patients with advanced melanoma. Methods In a phase I, 3+3 dose escalation trial, patients with metastatic or unresectable melanoma received treme in combination with MEDI3617. The primary objectives of the study were safety and determination of recommended phase II dose (RP2D). The secondary objectives included determination of 6-month and 1-year overall survival and best overall response rate. Immune cell populations and soluble factors were assessed in peripheral blood and metastatic tumors using Fluorescence activated cell sorting (FACS), Luminex, and multiplexed immunofluorescence. Results Fifteen patients (median age: 62) were enrolled in the study (3 patients in cohort 1: treme at 10 mg/kg and MEDI3617 at 200 mg; and 12 patients in cohort 2: treme at 10 mg/kg and MEDI3617 at 600 mg). The most common all-grade treatment-related adverse events were rash, pruritus, fatigue, and extremity edema. No dose-limiting toxicities were observed. Cohort 2 was determined to be the RP2D. There were no patients with confirmed immunerelated complete response or immune-related partial response. Six of 15 patients had immune-related stable disease, resulting in a disease control rate of 0.40 (95% CI 0.16 to 0.68). An increase in frequencies of circulating inducible T-cell costimulator (ICOS) + and human leukocyte antigen (HLA)-DR + CD4 + and CD8 + T cells and production of Interleukin-2 and Interleukin-10 was observed post therapy. Conclusions Tremelimumab in combination with MEDI3617 is safe in patients with advanced melanoma. Angiopoietin-2 inhibition in combination with immune checkpoint inhibition warrants further exploration. Trial registration number NCT02141542.
Purpose: Invariant NKT cells (iNKT) are innate-like CD1drestricted T cells with immunoregulatory ... more Purpose: Invariant NKT cells (iNKT) are innate-like CD1drestricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFNg production, and iNKT IFNg production may stratify for survival. Previous clinical trials using iNKT cell activating ligand a-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB-IV melanoma. Experimental Design: Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 in vitro to obtain up to approximately 10 9 cells. Results: Expanded iNKT cells produced IFNg, but limited or undetectable IL4 or IL10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1-2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMCs after some infusions, particularly when GM-CSF was also given. IFNg responses to a-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 8 evaluated patients. Three patients have died, three were progression-free at 53, 60, and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters. Conclusions: Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential. Clin Cancer Res; 23(14); 3510-9.
Clinical Breast Cancer, Apr 1, 2012
Little is known about the quality of life of women living long term with metastatic breast cancer... more Little is known about the quality of life of women living long term with metastatic breast cancer. We conducted a survey of women living with metastatic breast cancer for 5 years or longer. Although overall quality of life appeared quite favorable, some women reported substantial depression and/or anxiety about their disease. Ongoing work to address the needs of this growing population is warranted. Introduction: Psychosocial distress is common after a diagnosis of breast cancer. Little is known about the psychosocial adjustment of women living long term with metastatic breast cancer. Methods: We conducted a cross-sectional survey of women living with metastatic breast cancer for 5 years or longer. The survey included demographic and medical history, the Hospital Anxiety and Depression Scale (HADS), the Revised Impact of Events Scale (IES-R), the Functional Assessment of Cancer Therapy-Breast (FACT-Breast), and the Duke-University of North Carolina (UNC) Functional Social Support (DUFSS) Questionnaire. Demographic and disease characteristics were assessed by using the Wilcoxon rank sum test and the Fisher exact test. The relationships between IES-R, DUFSS, and the HADS were assessed by using the Spearman correlation coefficients. Statistical tests were 2-sided, with significance defined as P Յ .05. Results: Eighteen (64%) of 28 eligible women completed the survey. Women who completed the survey were more likely to have had node-positive disease (2P ϭ .0007), to had taken adjuvant therapy (2P ϭ .01), and to have had hormone-receptor positive disease than women who did not (2P ϭ .04). Among those who completed the survey, data from the FACT-Breast and the DUFSS indicated that women are physically functioning well but still face significant emotional challenges. Results from the HADS indicated that 2 (11.1%) of 18 women were depressed and that 2 (11.1%) of 18 women were anxious. Six (33%) of 18 women had scores on the IES-R Scale that indicated a powerful impact of traumatic stress on the ability to function. In the total sample of 18, the IES-R was significantly correlated with the HADS-Anxiety score (Spearman correlation, 0.81; 2P ϭ .0002) but not with the HADS-Depression score (Spearman correlation, 0.40; 2P ϭ .12). Conclusions: Although overall quality of life is good in this population of women living long term with metastatic breast cancer, there is a subset of women who are dealing with significant anxiety and depression, and a larger group who are experiencing burdensome sadness, hopelessness, and apprehension about their disease. Ongoing work to address the needs of this population is warranted.
Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopat... more Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n ¼ 1), hepatitis (n ¼ 2), and uveitis (n ¼ 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8 þ and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7 þ/À /CD45RO þ cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. Cancer Immunol Res; 2(7); 632-42. Ó2014 AACR.
Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effect... more Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients. Ipilimumab plus bevacizumab (Ipi-Bev) increased tumor vascular expression of ICAM1 and VCAM1. Treatment also altered concentrations of many circulating cytokines and chemokines, including increases of CXCL10, IL1a, TNFa, CXCL1, IFNa2, and IL8, with decreases in VEGF-A in most patients. IL1a and TNFa induced expression of E-selectin, CXCL1, and VCAM1 on melanoma tumor-asso-ciated endothelial cells (TEC) in vitro and promoted adhesion of activated T cells onto TEC. VEGFA inhibited TNFa-induced expression of ICAM1 and VCAM1 and T-cell adhesion, which was blocked by bevacizumab. CXCL10 promoted T-cell migration across TEC in vitro, was frequently expressed by melanoma cells, and was upregulated in a subset of tumors in treated patients. Robust upregulation of CXCL10 in tumors was accompanied by increased T-cell infiltration. Ipi-Bev also augmented humoral immune responses recognizing targets in melanoma, tumor endothelial, and tumor mesenchymal stem cells. Our findings suggest that Ipi-Bev therapy augments immune recognition in the tumor microenvironment through enhancing lymphocyte infiltration and antibody responses. IL1a, TNFa, and CXCL10, together with VEGF neutralization, contribute to Ipi-Bev-induced melanoma immune recognition.
Journal of Clinical Investigation, Mar 1, 2023
Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused b... more Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused by severe UV-induced mutations or expression of Merkel cell polyomavirus (MCPyV) large and small T antigens (LT and ST). Despite deep genetic differences between MCPyV-positive and -negative subtypes, current clinical diagnostic markers are indistinguishable and the expression profile of MCC tumors is unexplored. Methods: Here we leveraged bulk and single-cell RNA sequencing of patient-derived tumor biopsies and cell lines to explore the underlying expressional environment of MCC. Results: Strikingly, MCC samples could be separated into expressional subtypes that were independent of MCPyV-status. Instead, we observed an inverse correlation between a NE gene signature and Hippo pathway transcription factors Yes1-associated transcriptional regulator (YAP1) and WW domain containing transcriptional regulator (WWTR1). This inverse correlation was broadly present at the transcript and protein levels in the tumor biopsies as well as in established and patient-derived cell lines. Mechanistically, expression of YAP1 or WWTR1 in a MCPyV-positive MCC cell line induced cell-cycle arrest at least in part through TEADdependent transcriptional repression of MCPyV LT. Conclusion: These findings identify a previously unrecognized heterogeneity in NE gene expression within MCC and support a model of YAP1/WWTR1 silencing as essential for the development of MCPyV-positive MCC.
OncoImmunology, Mar 13, 2018
The combination of CTLA-4 blockade ipilimumab (Ipi) with VEGF-A blocking antibody bevacizumab (Be... more The combination of CTLA-4 blockade ipilimumab (Ipi) with VEGF-A blocking antibody bevacizumab (Bev) has demonstrated favorable clinical outcomes in patients with advanced melanoma. Galectin-3 (Gal-3) plays a prominent role in tumor growth, metastasis, angiogenesis, and immune evasion. Here we report that Ipi plus Bev (Ipi-Bev) therapy increased Gal-3 antibody titers by 50% or more in approximately one third of treated patients. Antibody responses to Gal-3 were associated with higher complete and partial responses and better overall survival. Ipi alone also elicited antibody responses to Gal-3 at a frequency comparable to the Ipi-Bev combination. However, an association of elicited antibody responses to Gal-3 with clinical outcomes was not observed in Ipi alone treated patients. In contrast to being neutralized in Ipi-Bev treated patients, circulating VEGF-A increased by 100% or more in a subset of patients after Ipi treatment, with most having progressive disease. Among the Ipi treated patients with therapy-induced Gal-3 antibody increases, circulating VEGF-A was increased in 3 of 6 nonresponders but in none of 4 responders as a result of treatment. Gal-3 antibody responses occurred significantly less frequently (3.2%) in a cohort of patients receiving PD-1 blockade where high pre-treatment serum Gal-3 was associated with reduced OS and response rates. Our findings suggest that anti-CTLA-4 elicited humoral immune responses to Gal-3 in melanoma patients which may contribute to the antitumor effect in the presence of an anti-VEGF-A combination. Furthermore, pre-treatment circulating Gal-3 may potentially have prognostic and predictive value for immune checkpoint therapy.
Menopause, Sep 1, 2010
Hot flashes are a major quality-of-life issue for breast cancer survivors, interrupting sleep, re... more Hot flashes are a major quality-of-life issue for breast cancer survivors, interrupting sleep, reducing quality of life, and diminishing treatment adherence to adjuvant endocrine therapies. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) are used widely but are only partially effective for hot flashes. Alternative strategies are needed. We hypothesized that augmentation of SSRI/SNRI therapy with hypnotic agents would optimize hot flash therapy by improving sleep and quality of life. Women with breast cancer or at high risk for developing the disease who had hot flashes in association with nocturnal awakenings were randomized to double-blinded treatment with zolpidem 10 mg or placebo for 5 weeks. SSRI/SNRI nonusers (81%) started venlafaxine XR 75 mg/day concurrently, whereas SSRI/SNRI users continued that therapy. We compared the proportion of responders, defined as study completers with improved subjective sleep quality (Pittsburgh Sleep Quality Index) and/or objectively assessed wake time after sleep onset on actigraphy, between groups. Of 53 women (aged 51 ± 8 y) randomized to zolpidem augmentation (n = 25) or placebo augmentation (n = 28), 38 completed the protocol (57% on placebo, 88% on zolpidem). More women augmented with zolpidem than placebo were responders on the sleep outcome (40% vs 14%; P = 0.035). Quality of life improved more with zolpidem than with placebo (P = 0.01). Treatment effects on hot flashes and mood did not differ between groups. Augmentation of SSRI/SNRI with zolpidem improves sleep and quality of life in breast cancer survivors with hot flashes and associated sleep disturbance. Adding a hypnotic agent to an SSRI/SNRI helps women to sleep through nighttime hot flashes. Treatments targeting sleep may be an important supplemental strategy to optimize well-being.
Cancer, Feb 12, 2016
BACKGROUNDExercise interventions improve fitness, functional capacity, and quality of life in pat... more BACKGROUNDExercise interventions improve fitness, functional capacity, and quality of life in patients with early‐stage breast cancer, but to the authors' knowledge there are few data regarding the feasibility or potential benefits of exercise in women with metastatic breast cancer.METHODSIndividuals with metastatic breast cancer were randomized 1:1 to a 16‐week moderate‐intensity exercise intervention or wait‐list control group. Intervention goals included 150 minutes of moderate‐intensity aerobic exercise per week. The baseline and 16‐week evaluations included a modified Bruce Ramp treadmill test, 7‐day Physical Activity Recall interview, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C‐30) questionnaire.RESULTSA total of 101 participants were randomized (48 to the intervention group and 53 to the control group). The median age of the participants was 49 years, the median time since the diagnosis of metastatic breast cancer was 1.1 years, and approximately 42% of participants were undergoing chemotherapy at the time of enrollment. Study attrition was higher in the intervention arm (14 participants vs 8 participants; P = .15). Women randomized to the exercise intervention experienced a nonsignificant increase with regard to minutes of weekly exercise (62.4 minutes vs 46.0 minutes; P = .17) and physical functioning (EORTC QLQ C30: 4.79 vs 0.93 [P = .23] and Bruce Ramp Treadmill test: 0.61 minutes vs 0.37 minutes [P = .35]) compared with control participants.CONCLUSIONSParticipation in an exercise intervention did not appear to result in significant improvements in physical functioning in a heterogeneous group of women living with advanced breast cancer. Given the significant benefits of exercise in women with early‐stage breast cancer, more work is needed to explore alternative interventions to determine whether exercise could help women with metastatic disease live more fully with fewer symptoms from disease and treatment. Cancer 2016;122:1169–77. © 2016 American Cancer Society.
Journal for ImmunoTherapy of Cancer, 2014
Background: Investigate the tumor diameter and density changes in advanced melanoma patients trea... more Background: Investigate the tumor diameter and density changes in advanced melanoma patients treated with ipilimumab plus bevacizumab, compare response rates based on different response criteria, and study association between these measures and survival. Methods: Twenty-one advanced melanoma patients with 59 measurable lesions treated in a phase 1 trial of ipilimumab plus bevacizumab were retrospectively studied. Tumor diameter and density were measured on baseline and first follow-up CT. Responses were assigned using RECIST, MASS and Choi criteria. Diameter and density measures and responses by these criteria were studied for the association with survival. Results: Twenty-three (39%) lesions and 7 (33%) patients met the Choi density criteria for response (≥15% density decrease) at the first follow-up. The response rates were 14% (3/21, 95% CI: 3-36%) by RECIST and MASS, and 52% (11/21, 95% CI: 30-74%) by Choi criteria, when both size and density criteria were used. Larger baseline tumor diameter was significantly associated with shorter progression-free survival (PFS) and overall survival (OS) (log-rank p = 0.001 and 0.003; respectively). Diameter or density changes, or responses by RECIST, MASS or Choi criteria at the first follow-up, were not associated with PFS or OS. Conclusion: Tumor density decrease meeting Choi criteria was noted in one-third of advanced melanoma patients at the first follow-up scan during ipilimumab plus bevacizumab therapy. While larger baseline tumor diameter was strongly associated with shorter survival, changes of diameter or density, or responses by three criteria did not predict survival. The role of density changes in evaluating response during ipilimumab and bevacizumab therapy for advanced melanoma remains to be further established.
Journal of Clinical Oncology, May 20, 2012
9084 Background: Physical activity (PA) interventions improve fitness, functional capacity, and q... more 9084 Background: Physical activity (PA) interventions improve fitness, functional capacity, and quality of life in patients with early-stage breast cancer. There are almost no data regarding the feasibility or potential benefits of PA in women with metastatic breast cancer (MBC). Our study evaluated the impact of a moderate-intensity PA intervention upon functional measures in patients with MBC. Methods: Participants were randomized 1:1 to a 16-week PA intervention or usual care control group. Eligibility included diagnosis of MBC, ECOG 0-1, and no active brain metastases. The intervention consisted of 4 weekly meetings with an exercise physiologist, followed by monthly in-person and weekly telephone-based meetings. The PA goal was 150 minutes per week. Baseline and 16-week evaluation included: modified Bruce treadmill test, 7-Day Physical Activity Recall Interview, and EORTC QLQ C-30 questionnaire. Results: 101 women enrolled between 9/06 and 3/11. Median age was 49 years, median time since diagnosis of MBC was 1.1 years, 48% of participants were on hormonal therapy and 42% on chemotherapy/biologic therapy. 69% completed all study measures (an additional 9% all but the final treadmill test). Attrition was higher in the intervention arm (30% vs. 16%, p=0.15). Outcome measures are shown in table below. Both groups experienced improvements in treadmill times. Intervention participants also reported improvements in physical functioning and increased minutes of weekly PA, with a trend toward significant differences between groups. Conclusions: Women with MBC participating in a PA intervention experienced consistent, but non-significant, trends toward improvements in functional measures. Our sample size was small, limiting power to evaluate the potential benefits of PA in women with MBC. Additional work is warranted, particularly since PA interventions appear feasible in this patient population. [Table: see text]
Annals of Surgical Oncology, 2009
Epidemiological evidence suggests that physical activity may affect breast cancer risk and other ... more Epidemiological evidence suggests that physical activity may affect breast cancer risk and other health outcomes. Little information is available regarding changes in activity after diagnosis and treatment of in-situ cancer. We enrolled 487 women with newly diagnosed ductal carcinoma-insitu (DCIS) in a longitudinal cohort study. Exercise behaviors were assessed at enrollment and at 18 months. Changes in exercise frequency over time were compared, and the impact of demographic and treatment-related variables was evaluated. Enrollment and 18-month exercise data were available for 391 women (80%). At enrollment, most women performed strenuous physical activity infrequently, and only half engaged in any type of exercise more than twice a week. Overall activity patterns did not change greatly over the course of the study. However, logistic regression modeling of changes in exercise revealed that women who underwent unilateral or bilateral mastectomy (hazard ratio [HR], 2.4; 95% confidence interval [95% CI], 1.3-4.4) and those who were anxious at enrollment (HR, 2.1; 95% CI, 1.1-4.1) were statistically significantly more likely to decrease exercise levels, and women who worked were significantly more likely to increase exercise over the course of the study (HR, 1.9; 95% CI, 1.1-3.3). Nonsignificant variables included age, reconstructive surgery, depressive symptoms, financial status, education, and tamoxifen use. A large proportion of women with newly diagnosed DCIS were inactive and remained so over time. Women who underwent mastectomy, as well as women who were more anxious, were more likely to decrease their level of physical activity. Women with DCIS might benefit from targeted interventions to increase physical activity. The number of women diagnosed with ductal carcinoma-in-situ (DCIS) each year has risen dramatically with the widespread use of screening mammography. 1,2 Survival after DCIS diagnosis is generally excellent with appropriate local management. Patients with DCIS are at increased risk of subsequent breast cancer events, but most of these patients will not die from breast cancer-related causes. In this setting, it is important to understand the impact of DCIS diagnosis and treatment on lifestyle factors associated with breast cancer risk and other health outcomes. Observational studies have demonstrated that physically active women are at lower risk of developing invasive and in situ breast cancers, and emerging data suggest that women who are physically active after diagnosis of invasive breast cancer have J. A. Ligibel,
Nature, Jul 5, 2017
Effective anti-tumor immunity in humans has been associated with the presence of T cells directed... more Effective anti-tumor immunity in humans has been associated with the presence of T cells directed at cancer neoantigens 1 , which are T cell epitopes with tumor-specific expression arising from nonsilent somatic mutations. They are highly immunogenic because they are not expressed in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumor immune response 2 , their systematic discovery and evaluation only became feasible with the recent availability of massively-parallel sequencing for detection of all coding mutations within tumors, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous HLA molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T cell populations and induce a broader repertoire of new T cell specificities in cancer patients, tipping the intratumoral balance in favor of enhanced tumor control. Here we demonstrate the feasibility, safety and immunogenicity of a vaccine that targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4 + and CD8 + T cells targeted 58 (60%) and 15 (16%), respectively, of the 97 unique neoantigens used across patients. These T cells discriminated mutated from wildtype antigens, and in some cases, directly recognized autologous tumor. Of 6 vaccinated patients, 4 had no recurrence at 25 months post-vaccination, while 2 with progressive disease were subsequently treated with anti-PD-1 therapy and experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint therapies.
Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts o... more Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. Patients and Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/ CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8 þ and CD8 þ /PD-1 þ /Ki-67 þ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.
Journal of integrative and complementary medicine, Mar 2, 2022
Introduction: Breast cancer patients undergoing chemotherapy experience multiple distressing symp... more Introduction: Breast cancer patients undergoing chemotherapy experience multiple distressing symptoms. The authors investigated the feasibility and potential benefits of auricular acupuncture during chemotherapy infusion in this population. Materials and Methods: Women with stage I-III breast cancer undergoing chemotherapy were enrolled and followed for three chemotherapy cycles. During the first cycle of chemotherapy that participants received after study enrollment, they were provided with educational materials. During the second and third cycles of chemotherapy after enrollment, they received auricular acupuncture. The primary outcome was feasibility, assessed by recruitment, retention, and completion of assessments. Secondary outcomes included symptom burden (Edmonton Symptom Assessment System-Revised Version) and anxiety (State-Trait Anxiety Inventory-State), assessed at four timepoints for each cycle: day 1, pre-education/acupuncture (T1); day 1, post-education/acupuncture (T2); day 2 (T3); and day 5 (T4). Nausea and vomiting (Multinational Association of Supportive Care in Cancer [MASCC] Antiemesis Tool) were assessed on days 2 and 5. Paired t test was used to compare patient-reported outcomes during cycle 1 (education) versus an average of outcomes during cycles 2 and 3 (acupuncture). Results: Twenty-six patients were enrolled, of which 24 completed all acupuncture sessions and 22 completed all outcome assessments. In cycles 2 and 3 versus cycle 1, participants experienced significant reductions in symptom burden (change from T1 to T4: -7.9 ± 13.6, p = 0.02), anxiety (change from T1 to T2: -3.3 ± 6.5, p = 0.02), and nausea severity on day 2 (-1.3 ± 2.6, p = 0.04). Conclusions: The delivery of auricular acupuncture during chemotherapy infusion was feasible and associated with reduction of symptom burden, anxiety, and nausea in breast cancer patients. Larger-scale clinical studies are needed to confirm these findings. Clinical Trial Registration number: NCT03170648.
Psycho-oncology, Sep 12, 2021
ObjectiveThe Healthy Living and Eating After Cancer Trial demonstrated that a clinic‐based weight... more ObjectiveThe Healthy Living and Eating After Cancer Trial demonstrated that a clinic‐based weight loss program reduced body weight, as compared with a waitlist control group, over 15 weeks. Here we report the impact of the weight loss intervention on health‐related quality‐of‐life outcomes at week 15, and maintenance of weight loss to week 30.MethodsThis trial randomized cancer survivors of solid tumors and hematologic malignancies (breast cancer: 76.7%) to a 15‐week group‐based weight loss program (n = 30) or a waitlist control group (n = 30). Participants were not blinded to group assignment. Participants completed a variety of health‐related quality‐of‐life outcome measures at baseline and week 15. From week 15 to week 30, participants initially randomized to the weight loss program were followed with no additional intervention, and participants initially randomized to the waitlist control group commenced the weight loss program.ResultsOver the 15 weeks, the weight loss program improved physical functioning (6.2 ± 2.9;p = 0.02;d = 0.31) and reduced insomnia symptoms (−17.1 ± 7.4;p = 0.03;d = −0.30) as measured by the EORTC QLQ‐C30, and sleep disturbance (−4.9 ± 1.6;p = 0.005;d = −0.40) as measured by PROMIS, compared to waitlist control. After a weight loss of 4.6 ± 3.9 kg, from week 15 to week 30, participants who were initially randomized to the weight loss program maintained their prior weight loss (+0.6 ± 3.5 kg) and participants who were initially randomized to the waitlist control group lost weight (−3.4 ± 2.9 kg;p &lt; 0.001).ConclusionsIn cancer survivors with overweight or obesity, a 15‐week clinic‐based weight loss program improved health‐related quality‐of‐life outcomes and produced sustained weight loss to week 30.
Cancer Immunology, Immunotherapy, Oct 28, 2011
Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation o... more Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I-IV patients and healthy controls by ELISPOT. A broad array of CD4 ? and CD8 ? cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific CD4 ? and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target.
Blood Advances
Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common aggressive non-H... more Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common aggressive non-Hodgkin lymphoma and a biologically heterogeneous disease. Despite the development of effective immunotherapies, the organization of the DLBCL tumor-immune microenvironment (TIME) remains poorly understood.We interrogated the intact TIME of 51 de novo DLBCLs with triplicate sampling to characterize 337 995 tumor and immune cells using a 27-plex antibody panel that captured cell lineage, architectural, and functional markers. We spatially assigned individual cells, identified local cell neighborhoods, and established their topographical organization in situ. We found that the organization of local tumor and immune cells can be modeled by 6 composite cell neighborhood types (CNTs). Differential CNT representation divided cases into 3 aggregate TIME categories: immune-deficient, dendritic cell–enriched (DC-enriched), and macrophage-enriched (Mac-enriched). Cases with immune-deficient TIMEs h...
Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), ye... more Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)–induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7–85) and 42 (range, 14–273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14–169) and 42 days (range, 14–315) days, the median time to onset of hypothyroidism: 63 (range, 21–190) and 63 (range, 14–489...
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Papers by Anita Giobbie-hurder