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Endoscopic tumor resection and intestinal defect repair are technically challenging leading to invasive surgery and colectomy performed for resection of benign polyps. In this study, we evaluated the use of an endoscopic overtube with bilateral tool channels for these procedures.Using a fresh porcine colorectum in a 3D ex vivo model, 3 cm lesions at the posterior wall of the transverse colon were removed by two different techniques: standard endoscopic submucosal dissection (ESD) technique (STD, n = 12) and ESD using the overtube with an endoscopic snare and grasper through the bilateral channels (OT, n = 12). Procedure times and the number of muscular injuries were evaluated. Using the same model, 5-10 mm full-thickness perforations within a 3 cm mucosal defect at the posterior wall of the transverse colon were closed by two different techniques: standard endoscopic closure technique (STD, n = 12) and endoscopic closure using the overtube with two graspers (OT, n = 12). The outcomes measured included bursting pressure and the number of endoscopic clips used for closure.Endoscopic resection of lesions was performed by the OT group in a significantly shorter total procedure time (STD vs. OT = median 38.9 min vs. 17.3, p 0.001) and with fewer muscular injuries (median 0 vs. 2, p = 0.002), compared with the STD group. After repair of intestinal defects, the OT group showed higher median bursting pressures (STD vs. OT = 11.2 mmHg vs. 57.1, p = 0.008) despite using fewer clips (median 13 vs. 10, p 0.001).This study demonstrates a novel traction technique with an endoscopic overtube using multiple instruments to remove lesions and repair intestinal defects in the colon more effectively. This endoscopic platform could provide a safe alternative to invasive surgical treatment.

Supplemental Table 2: Pathologic complete response rates by route of vaccine administration and ER status in 42 DCIS patients

Supplemental Figure 1: CONSORT diagram of the 58 patients enrolled in the vaccine trial. A total of 54 were randomized to one of the three vaccination routes. After the twenty second patient completed the vaccine, subsequent ER positive patients were treated with concurrent anti-estrogen therapy.

Supplemental Figure 4: The CD4pos Th1 immune response in the peripheral blood pre-vaccination and post-vaccination by clinical response (

Supplemental Table 1: Overall immune response detected in the peripheral blood by route of vaccine administration and ER status

Purpose: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection.Experimental Design: Fifty-four HER2pos patients [42 pure ductal carcinoma in situ (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n = 19), IN (n = 19), or ILN (n = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in vitro sensitization assay. Pathologic response was assessed in resected surgical specimens.Results: Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; P = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n = 12) and who did not achieve pCR (n = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire (P = 0.03) and cumulative response (P = 0.04).Conclusions: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. Clin Cancer Res; 23(12); 2961–71. ©2016 AACR.

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Endoscopic submucosal dissection (ESD) is a challenging procedure for the removal of colorectal tumors, especially tumors located in the right colon. The use of traction could make this procedure technically easier and reduce procedure times and complication rates. In this study, we demonstrated the feasibility and utility of a traction technique utilizing an endoscopic snare through an overtube, a double-balloon endolumenal interventional platform (DEIP) in a porcine colorectal model. A total of 120 procedures were performed using three different techniques: standard ESD technique (STD), ESD with DEIP (DEIP alone), and ESD with DEIP and a snare (DEIP + Snare). The snare was passed inside the overtube and used as a grasper on the tissue to provide traction. Lesions 3 or 4 cm in diameter were removed with a 5 mm margin from the anterior and posterior walls of the proximal Transverse Colon, the Hepatic Flexure, and the posterior wall of the Cecum. The outcomes measured included procedure times and the number of muscularis propria injuries. The DEIP + Snare group showed significantly shorter total procedure and submucosal dissection times for lesions in all locations (median 28.1 min (DEIP + Snare, n = 32) vs 39.8 (STD, n = 32) vs 39.7 (DEIP alone, n = 32); 7.5 min vs 25.3 vs 25.1) and had fewer muscularis propria injuries (median 0 [range 0–2] vs 2 [0–7] vs 1 [0–6]) than the two other groups. Larger lesions (4 cm) were successfully removed by regrasping the tissue in DEIP + Snare group, which showed significantly shorter total procedure time [31.4 min (DEIP + Snare, n = 8) vs 40.1 (STD, n = 8) vs 45.6 (DEIP alone, n = 8)] and submucosal dissection time (12.3 min vs 27.6 vs 29.1) than the two other groups. ESD traction technique with an endolumenal platform and snare enables faster removal of large polyps in the right colon with fewer injuries than standard methods of ESD.

Treatment of inflammatory bowel disease (IBD) is often multidimensional, requiring both medical and surgical therapies at different times throughout the course of the disease. Both medical and surgical treatments may be used in the acute setting, during a flare, or in a more elective maintenance role. These treatments should be planned as complementary and synergistic. Gastroenterologists and colorectal surgeons should collaborate to create a cohesive treatment plan, arranging the sequence and timing of various treatments. This article reviews the anticipated postoperative recovery after surgical treatment of IBD, possible postoperative complications, and considerations of timing surgery with medical therapy.

Crohn's disease (CD) is a pan-intestinal disease of the gastrointestinal tract characterized by inflammatory, penetrating, and fibrostenotic phenotypes. Fibrostenotic stricture formation, without inflammatory or penetrating disease, is a common complication in CD, primarily affecting the small intestine and leading to small bowel obstruction. Because there is no medical therapy that prevents or reverses stricturing disease, endoscopic and surgical treatments are the mainstays of treatment, indicated to palliate symptoms and treat the complications. Endoscopic approaches include dilation, stricturotomy, and endoscopic stenting. Surgical options include resection, intestinal bypass, and various strictureplasty techniques. In this article, we will focus on the treatment of stricturing CD: specifically, the considerations important in choosing between different treatment options and technical tips to deal with complicated disease.

Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP+Ig), and ESD using IgE (DESP+IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig’s reach. Compared with the STD, both DESP+Ig and DESP+IgE showed significantly shorter procedure time (STD vs. DESP+Ig vs. DESP+IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP+IgE had a shorter procedure time than the DESP+Ig (p=0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon.

Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP + Ig), and ESD using IgE (DESP + IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig’s reach. Compared with the STD, both DESP + Ig and DESP + IgE showed significantly shorter procedure time (STD vs. DESP + Ig vs. DESP + IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP + IgE had a shorter procedure time than the DESP + Ig (p = 0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon.

Endoscopic submucosal dissection (ESD) is a challenging procedure for the removal of colorectal tumors, especially tumors located in the right colon. The use of traction could make this procedure technically easier and reduce procedure times and complication rates. In this study, we demonstrated the feasibility and utility of a traction technique utilizing an endoscopic snare through an overtube, a double-balloon endolumenal interventional platform (DEIP) in a porcine colorectal model.A total of 120 procedures were performed using three different techniques: standard ESD technique (STD), ESD with DEIP (DEIP alone), and ESD with DEIP and a snare (DEIP + Snare). The snare was passed inside the overtube and used as a grasper on the tissue to provide traction. Lesions 3 or 4 cm in diameter were removed with a 5 mm margin from the anterior and posterior walls of the proximal Transverse Colon, the Hepatic Flexure, and the posterior wall of the Cecum. The outcomes measured included procedure times and the number of muscularis propria injuries.The DEIP + Snare group showed significantly shorter total procedure and submucosal dissection times for lesions in all locations (median 28.1 min (DEIP + Snare, n = 32) vs 39.8 (STD, n = 32) vs 39.7 (DEIP alone, n = 32); 7.5 min vs 25.3 vs 25.1) and had fewer muscularis propria injuries (median 0 [range 0-2] vs 2 [0-7] vs 1 [0-6]) than the two other groups. Larger lesions (4 cm) were successfully removed by regrasping the tissue in DEIP + Snare group, which showed significantly shorter total procedure time [31.4 min (DEIP + Snare, n = 8) vs 40.1 (STD, n = 8) vs 45.6 (DEIP alone, n = 8)] and submucosal dissection time (12.3 min vs 27.6 vs 29.1) than the two other groups.ESD traction technique with an endolumenal platform and snare enables faster removal of large polyps in the right colon with fewer injuries than standard methods of ESD.

Purpose: Vaccination with HER2 peptide-pulsed DC1s stimulates a HER2-specific T-cell response. This randomized trial aimed to establish safety and evaluate immune and clinical responses to vaccination via intralesional (IL), intranodal (IN), or both intralesional and intranodal (ILN) injection. Experimental Design: Fifty-four HER2pos patients [42 pure ductal carcinoma in situ (DCIS), 12 early invasive breast cancer (IBC)] were enrolled in a neoadjuvant HER2 peptide-pulsed DC1 vaccine trial. Patients were randomized to IL (n = 19), IN (n = 19), or ILN (n = 16) injection. Immune responses were measured in peripheral blood and sentinel lymph nodes by ELISPOT or in vitro sensitization assay. Pathologic response was assessed in resected surgical specimens. Results: Vaccination by all injection routes was well tolerated. There was no significant difference in immune response rates by vaccination route (IL 84.2% vs. IN 89.5% vs. ILN 66.7%; P = 0.30). The pathologic complete response (pCR) rate was higher in DCIS patients compared with IBC patients (28.6% vs. 8.3%). DCIS patients who achieved pCR (n = 12) and who did not achieve pCR (n = 30) had similar peripheral blood anti-HER2 immune responses. All patients who achieved pCR had an anti-HER2 CD4 immune response in the sentinel lymph node, and the quantified response was higher by response repertoire (P = 0.03) and cumulative response (P = 0.04). Conclusions: Anti-HER2 DC1 vaccination is a safe and immunogenic treatment to induce tumor-specific T-cell responses in HER2pos patients; immune and clinical responses were similar independent of vaccination route. The immune response in the sentinel lymph nodes, rather than in the peripheral blood, may serve as an endpoint more reflective of antitumor activity. Clin Cancer Res; 23(12); 2961–71. ©2016 AACR.

Colonoscopy is a common procedure performed for screening, diagnostic, or therapeutic indications; nevertheless, it is an invasive procedure that has associated risks. Complications of colonoscopy can be divided into four main categories: (1) bleeding, (2) postpolypectomy syndrome, (3) perforation, and (4) rarely, solid organ injury. In this review, we discuss strategies to avoid and treat complications of colonoscopy. Diligent biopsy and use of electrocautery and avoiding looping and blind advancement of the colonoscope minimize the risk of these complications. Management of complications ranges from non-operative conservative management, to minimally invasive endoscopic or laparoscopic techniques, to operative exploration.

HER2 overexpression leads to downregulation of MHC class-I. CD4+ Th1 cytokines, IFNγ and TNFα, and monoclonal antibodies, trastuzumab and pertuzumab, restore MHC class-I expression, and enable CD8+ recognition and cytolysis. Restoration of the anti-HER2 CD4+ Th1 immune response in combination with HER2 targeted therapy appear to be critical to successful anti-HER2 CD8+ immunotherapy.

We previously demonstrated a progressive loss of the anti-human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) response during HER2pos breast tumorigenesis. This loss is associated with residual disease following neoadjuvant therapy and increased risk of recurrence. In this study, we assessed the fate of anti-HER3 Th1 immunity during breast tumorigenesis. Peripheral blood from 131 subjects, including healthy donors (HDs), patients with benign breast disease (BD), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC), was collected. Interferon (IFN)-γpos immune responses to four HER3-derived major histocompatibility complex (MHC) class II promiscuous peptides were tested via enzyme-linked immunosorbent (ELISPOT) assays, and three immune response parameters were compared: anti-HER3 (i) responsivity, or proportion of subjects responding to at least one peptide; (ii) repertoire, or number of responding peptides; and (iii) cumulative response, or summed peptide response. A significant decline in anti-HER3 Th1 response was observed going from HDs to IBC patients; patients with triple-negative breast cancer (TNBC) demonstrated the lowest responses. HDs had significantly higher Th1 responses versus estrogen receptor (ER)pos IBC and TNBC patients across all three immune parameters; HER2pos IBC patients displayed responses similar to HDs and BDs. Patients with recurrent breast cancer and residual disease following neoadjuvant therapy demonstrated significantly lower anti-HER3 Th1 immunity compared with patients without recurrence or with a pathologic complete response to neoadjuvant therapy. Anti-HER3 CD4+ Th1 responses decline during breast tumorigenesis, particularly in TNBC. Attempts to immunologically restore depressed responses in vulnerable subgroups may help mitigate recurrence.

National guidelines endorse adjuvant chemotherapy ± radiotherapy (C ± RT) for early-stage gastric cancer (ESGC). Compliance with these guidelines and the specific impact of adjuvant C ± RT on overall survival (OS) in ESGC have not been extensively explored. The National Cancer Data Base was queried for stage IB-II gastric adenocarcinoma patients undergoing gastrectomy (1998–2011). Multivariable modeling identified factors associated with adjuvant C ± RT receipt and compared risk-adjusted OS by treatment type (i.e., adjuvant therapy versus surgery alone). Of 23,461 ESGC patients (1998–2011), 79.4 % and 20.6 % received surgery alone and adjuvant C ± RT (chemoradiotherapy 17.7 %; chemotherapy alone 2.9 %), respectively. Predictors of adjuvant C ± RT receipt included age

In patients with HER2-expressing breast cancer many develop resistance to HER2 targeted therapies. We show that high and intermediate HER2-expressing cancer cell lines are driven toward apoptosis and tumor senescence when treated with either CD4+ Th1 cells, or Th1 cytokines TNF-α and IFN-γ, in a dose dependent manner. Depletion of HER2 activity by either siRNA or trastuzumab and pertuzumab, and subsequent treatment with either anti-HER2 Th1 cells or TNF-α and IFN-γ resulted in synergistic increased tumor senescence and apoptosis in cells both sensitive and cells resistant to trastuzumab which was inhibited by neutralizing anti-TNF-α and IFN-γ. Th1 cytokines induced minimal senescence or apoptosis in triple negative breast cancer cells (TNBC); however, inhibition of EGFR in combination with Th1 cytokines sensitized those cells causing both senescence and apoptosis. TNF-α and IFN-γ led to increased Stat1 phosphorylation through serine and tyrosine sites and a compensatory reduction in Stat3 activation. Single agent IFN-γ enhanced Stat1 phosphorylation on tyrosine 701 and similar effects were observed in combination with TNF-α and EGFR inhibition. These results demonstrate Th1 cytokines and antioncodriver blockade cooperate in causing tumor senescence and apoptosis in TNBC and HER2-expressing breast cancer, suggesting these combinations could be explored as non-cross-reactive therapy preventing recurrence in breast cancer. Fil: Rosemblit, Cinthia. H. Lee Moffitt Cancer Center; Estados Unidos. University of Pennsylvania; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Datta, Jashodeep. University of Pennsylvania; Estados Unidos Fil: Lowenfeld, Lea. University of Pennsylvania; Estados Unidos Fil: Xu, Shuwen. University of Pennsylvania; Estados Unidos Fil: Basu, Amrita. H. Lee Moffitt Cancer Center; Estados Unidos Fil: Kodumudi, Krithika. H. Lee Moffitt Cancer Center; Estados Unidos Fil: Wiener, Doris. H. Lee Moffitt Cancer Center; Estados Unidos Fil: Czerniecki, Brian J.. H. Lee Moffitt Cancer Center; Estados Unidos. University of Pennsylvania; Estados Unidos

National guidelines advocate use of multimodality therapy (MMT) for treatment of T4 gastric cancer (T4GC). Prior studies demonstrate poor compliance with these guidelines. We sought to assess treatment trends and association between different treatment approaches and overall survival (OS) in a large cohort of U.S. patients. Patients diagnosed with clinical T4 gastric adenocarcinoma were selected from the National Cancer Data Base (1998–2011). Temporal trends, risk factors associated with failure to receive treatment, and effect of treatments on OS were assessed. Of 4369 patients with T4GC, only 15 % (n = 652) received MMT. Treatment with MMT increased over time, and was utilized in 25 % of patients after 2006. Older age, African American race, nonprivate insurance, proximal tumor location, and clinical node-negative disease were associated with failure to receive surgery; older age, female sex, poorly differentiated tumor grade, clinical node-negative disease, and prolonged postoperative length of stay were associated with failure to complete MMT in patients who underwent surgical resection. Median OS was longest in patients receiving MMT (19.2 months), and was similarly poor in patients undergoing surgical resection (9.0 months) or nonsurgical therapy (8.3 months; p

HER2-directed therapies are less effective in patients with ERpos compared to ERneg breast cancer, possibly reflecting bidirectional activation between HER2 and estrogen signaling pathways. We investigated dual blockade using anti-HER2 vaccination and anti-estrogen therapy in HER2pos/ERpos early breast cancer patients. In pre-clinical studies of HER2pos breast cancer cell lines, ERpos cells were partially resistant to CD4+ Th1 cytokine-induced metabolic suppression compared with ERneg cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ERpos, but not ERneg, cell lines. In two pooled phase-I clinical trials, patients with HER2pos early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2pos/ERpos patients were treated with or without concurrent anti-estrogen therapy. The anti-HER2 Th1 immune response measured in the peripheral blood significantly increased following vaccination, but was similar across the three treatment groups (ERneg vaccination alone, ERpos vaccination alone, ERpos vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ERpos patients treated with combination anti-HER2 vaccination plus anti-estrogen therapy compared to those treated with anti-HER2 vaccination alone. Similar rates of pathologic complete response (pCR) were observed in vaccinated ERneg patients and vaccinated ERpos patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ERpos patients who did not receive anti-estrogen therapy (4.0%, p = 0.03). Since pCR portends long-term favorable outcomes, these results support additional clinical investigations using HER2-directed vaccines in combination with anti-estrogen treatments for ERpos/HER2pos DCIS and invasive breast cancer.

The immune response against cancers, including breast cancer, are shown to play a critical role in survival. Vaccines have long been hailed as the most effective medical intervention to prevent a disease. While cancer vaccines have mostly been used therapeutically with little success in established breast cancer, their role in early breast cancer appears more promising, and primary prevention of breast cancer by vaccination is now being contemplated. The selection of vaccine targets is a critical issue, since unlike cancers with established viral etiology (e.g. cervical cancer), there is no single cause of breast cancer. Instead, there are multiple subsets of breast cancers including: Luminal A, Luminal B, HER-2, and subsets of basal-like cancer. Each of these types can be antigenically distinct, and present immune targets that may be phenotype-specific or to some degree overlapping between subsets. Three general categories of such targets are being developed as breast cancer vaccines. These include oncodrivers, breast tissue specific antigens, and cancer specific antigens. It is likely that combinations of these vaccine approaches may be best for treatment and prevention. Carriers of high-risk breast cancer mutations represent a potential target patient population for prevention. However, approximately 85 % of breast cancers occur in patients with no identified risk. Recent evidence suggests that a loss of natural immune responses against oncodrivers may identify patients at risk for early breast cancer. Devising tests to identify subjects at risk for breast cancer are needed since these will allow us to focus prevention efforts, including vaccination, on those individuals where such resources are most needed. Preventive breast cancer vaccines may be achievable with our improved understanding of breast cancer biology, and the immune response in breast cancer.

HER2 overexpression leads to downregulation of MHC class-I. CD4(+) Th1 cytokines, IFNγ and TNFα, and monoclonal antibodies, trastuzumab and pertuzumab, restore MHC class-I expression, and enable CD8(+) recognition and cytolysis. Restoration of the anti-HER2 CD4(+) Th1 immune response in combination with HER2 targeted therapy appear to be critical to successful anti-HER2 CD8(+) immunotherapy.

Introduction A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4+ T-helper type 1 (Th1) immune responses is observed in HER2pos-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C. Methods Anti-HER2 Th1 responses in 87 HER2pos-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/106 cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization. Results Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2pos-IBC patients (n = 22) did not improve globally in T + C-treated HER2pos-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C — utilized in 61.5 % — was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/106, p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ+ immune disparity was mediated by anti-HER2 CD4+T-bet+IFN-γ+ (i.e., Th1) — not CD4+GATA-3+IFN-γ+ (i.e., Th2) — phenotypes, and not attributable to non-pCR patients’ immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/106, p = 0.014) improved significantly following HER2-pulsed DC1 vaccination. Conclusions Anti-HER2 CD4+ Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically “fixed” and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0584-1) contains supplementary material, which is available to authorized users.

HER2-directed therapies are less effective in patients with ERpos compared to ERneg breast cancer, possibly reflecting bidirectional activation between HER2 and estrogen signaling pathways. We investigated dual blockade using anti-HER2 vaccination and anti-estrogen therapy in HER2pos/ERpos early breast cancer patients. In pre-clinical studies of HER2pos breast cancer cell lines, ERpos cells were partially resistant to CD4+ Th1 cytokine-induced metabolic suppression compared with ERneg cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ERpos, but not ERneg, cell lines. In two pooled phase-I clinical trials, patients with HER2pos early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2pos/ERpos patients were treated with or without concurrent anti-estrogen therapy. The anti-HER2 Th1 immune response measured in the peripheral blood significantly increased following vaccination, but was similar across the three treatment groups (ERneg vaccination alone, ERpos vaccination alone, ERpos vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ERpos patients treated with combination anti-HER2 vaccination plus anti-estrogen therapy compared to those treated with anti-HER2 vaccination alone. Similar rates of pathologic complete response (pCR) were observed in vaccinated ERneg patients and vaccinated ERpos patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ERpos patients who did not receive anti-estrogen therapy (4.0%, p = 0.03). Since pCR portends long-term favorable outcomes, these results support additional clinical investigations using HER2-directed vaccines in combination with anti-estrogen treatments for ERpos/HER2pos DCIS and invasive breast cancer.

Introduction: We have developed an autologous HER2-pulsed dendritic cell (DC) vaccine that induces robust T-cell responses in early breast cancer. We have also previously demonstrated anti-HER2 Th1 responses to select class II peptides are preferentially lost early in HER2pos breast tumorigenesis. We aimed to compare peptide-specific Th1 responses between pathologic complete (pCR) and incomplete responders ( Methods: Patients with HER2pos DCIS (n = 37) or stage I invasive breast cancer (IBC) (n = 10) received neoadjuvant HER2-pulsed DC vaccine prior to surgery. Specimens were examined for residual disease on pathology. CD4 Th1 responses to 6 HER2 Class II peptides (p42-56, p98-114, p328-345, p776-790, p927-941, p1166-1180) were measured using IFN-γ production by ELISPOT. Th1 response metrics were: (1) anti-HER2 responsivity, (2) response repertoire (i.e. no. of reactive peptides), and (3) cumulative response. Th1 responses post-vaccination were compared between pCR (n = 11) and Results: Forty-three of 47 (91.5%) vaccinated subjects mounted CD4 Th1 responses post-vaccination. Eleven of 47 (23.4%) achieved pCR; no significant difference in pCR rates were observed between IBC and DCIS patients (10% vs 27.0%; p = 0.41). pCR and Conclusion: HER2-pulsed DC vaccination induces pathologic responses in early breast cancer patients, supporting further clinical development. The key immunogenic HER2 class II peptides that appear to drive pCR following DC vaccination are incidentally lost very early in tumorigenesis, suggesting that immune restoration targeting these select peptides may enable control of early breast cancer. Citation Format: Megan E. Fracol, Jashodeep Datta, Shuwen Xu, Lea Lowenfeld, Elizabeth Fitzpatrick, Carolyn Mies, Paul J.L. Zhang, Robert E. Roses, Carla Fisher, Brian J. Czerniecki. HER2 peptide-specific immunogenicity correlates with pathologic response following HER2-pulsed dendritic cell vaccination for early breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2489. doi:10.1158/1538-7445.AM2015-2489

BACKGROUND: We have previously demonstrated a loss of anti-HER2 CD4 T-helper type 1 responses (Th1resp) in HER2+ invasive breast cancer (IBC) pts relative to healthy donors. Compared with pathologic complete response (pCR) after neoadjuvant trastuzumab/chemotherapy (T/C), residual disease at surgery ( METHOD: Th1resp were generated from PBMCs pulsed with 6 HER2 class II peptides by measuring IFN-γ production via ELISPOT, and compared between HER2+ IBC groups. Th1resp metrics were anti-HER2 responsivity, no. of reactive peptides (repertoire), and cumulative response across 6 peptides (spots/10^6 cells). Th1resp of RESULTS: The study comprised 85 pts. The diminished anti-HER2 Th1resp in treatment-naïve HER2+ IBC pts (n = 21) - assessed by responsivity, repertoire, or cumulative response - did not improve globally in T/C-treated IBC pts (n = 64). Within this T/C-treated cohort, neoadjuvant T/C receipt (60.9%) was associated with higher repertoire (1.5 vs 0.7; p = 0.04), but not responsivity or cumulative response, compared with adjuvant T/C. CONCLUSION: Beyond the known association between ER status and pathologic response following neoadjuvant T/C in HER2+ breast cancer, we identify a novel correlation between Note: This abstract was not presented at the meeting. Citation Format: Jashodeep Datta, Erik Berk, Shuwen Xu, Elizabeth Fitzpatrick, Lea Lowenfeld, Noah Goodman, David Lewis, Robert E. Roses, Angela DeMichele, Brian J. Czerniecki. Depressed anti-HER2 CD4 Th1 responses correlate with residual disease following neoadjuvant therapy in HER2+ breast cancer patients and can be restored by dendritic cell vaccination. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1308. doi:10.1158/1538-7445.AM2015-1308