Jashodeep Datta

Dendritic cell-based vaccines: barriers and opportunities.

Dendritic cells (DCs) have several characteristics that make them an ideal vehicle for tumor vaccines, and with the first US FDA-approved DC-based vaccine in use for the treatment of prostate cancer, this technology has become a promising new therapeutic option. However, DC-based vaccines face several barriers that have limited their effectiveness in clinical trials. A major barrier includes the activation state of the DC. Both DC lineage and maturation signals must be selected to optimize the antitumor response and overcome immunosuppressive effects of the tumor microenvironment. Another barrier to successful vaccination is the selection of target antigens that will activate both CD8(+) and CD4(+) T cells in a potent, immune-specific manner. Finally, tumor progression and immune dysfunction limit vaccine efficacy in advanced stages, which may make DC-based vaccines more efficacious in treating early-stage disease. This review underscores the scientific basis and advances in the development of DC-based vaccines, focuses on current barriers to success and highlights new research opportunities to address these obstacles.

Implications of inadequate lymph node staging in resectable gastric cancer: A contemporary analysis using the National Cancer Data Base

National guidelines recommend examination of ≥ 15 lymph nodes for adequate staging of resectable gastric adenocarcinoma (GA). The relevance of these guidelines, which were established before the increasing use of multimodality therapy, and the impact of inadequate lymph node staging (LNS) in a contemporary cohort have not been extensively explored.

Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

Genomic profiling has identified several molecular oncodrivers in breast tumorigenesis. A thorough understanding of endogenous immune responses to these oncodrivers may provide insights into immune interventions for breast cancer (BC). We investigated systemic anti-HER2/neu CD4+ T-helper type-1 (Th1) responses in HER2-driven breast tumorigenesis. A highly significant stepwise Th1 response loss extending from healthy donors (HD), through HER2pos-DCIS, and ultimately to early stage HER2pos-invasive BC patients was detected by IFNγ ELISPOT. The anti-HER2 Th1 deficit was not attributable to host-level T-cell anergy, loss of immune competence, or increase in immunosuppressive phenotypes (Treg/MDSCs), but rather associated with a functional shift in IFNγ:IL-10-producing phenotypes. HER2high, but not HER2low, BC cells expressing IFNγ/TNF-α receptors were susceptible to Th1 cytokine-mediated apoptosis in vitro, which could be significantly rescued by neutralizing IFNγ and TNF-α, suggesting that abrogation of HER2-specific Th1 may reflect a mechanism of immune evasion in HER2-driven tumorigenesis. While largely unaffected by cytotoxic or HER2-targeted (trastuzumab) therapies, depressed Th1 responses in HER2pos-BC patients were significantly restored following HER2-pulsed dendritic cell (DC) vaccinations, suggesting that this Th1 defect is not “fixed” and can be corrected by immunologic interventions. Importantly, preserved anti-HER2 Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy, while depressed responses were observed in patients incurring locoregional/systemic recurrence following trastuzumab/chemotherapy. Monitoring anti-HER2 Th1 reactivity following HER2-directed therapies may identify vulnerable subgroups at risk of clinicopathologic failure. In such patients, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 CD4+ Th1 immunity may decrease the risk of recurrence and thus warrant further investigation.

Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy.

Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.

Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring

IMPORTANCE There is a paucity of immune signatures identifying patients with human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer (IBC) at risk for treatment failure following trastuzumab and chemotherapy. OBJECTIVE To determine whether circulating anti-HER2 CD4-positive (CD4+) T-helper type 1 (Th1) immunity correlates with recurrence in patients with completely treated HER2-positive IBC. DESIGN, SETTING, AND PARTICIPANTS Hypothesis-generating exploratory translational analysis at a tertiary care referral center of patients with completely treated HER2-positive IBC with median (interquartile range) follow-up of 44 (31) months. Anti-HER2 Th1 responses were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II-promiscuous peptides via interferon-γ (IFN-γ) enzyme-linked immunospot assay. MAIN OUTCOMES AND MEASURES T-helper type 1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFCs]/106 cells). Anti-HER2 Th1 responses in treatment-naive patients (used as an immunologic baseline) were compared with those in patients completing trastuzumab and chemotherapy; in the latter group, analyses were stratified by recurrence status. Recurrence was defined as any locoregional or distant breast event, or both. Cox regression analysis estimated the instantaneous hazard of recurrence (ie, disease-free survival [DFS]) stratified by anti-HER2 Th1 responsivity. RESULTS In 95 women with HER2-positive IBC (median [range] age, 49 [24-85] years; 22 treatment-naive, 73 treated with trastuzumab and chemotherapy), depressed anti-HER2 Th1 responsivity (recurrence, 2 of 25 [8%], vs nonrecurrence, 40 of 48 [83%]; P < .001), mean (SD) repertoire (0.1 [0.1] vs 1.5[0.2]; P < .001), and mean (SD) cumulative response (14.8 [2.0] vs 80.2 [11.0] SFCs/106 cells; P < .001) were observed in patients incurring recurrence (n = 25) compared with patients without recurrence (n = 48). After controlling for confounding, anti-HER2 Th1 responsivity remained independently associated with recurrence (P < .001). This immune disparity was mediated by anti-HER2 CD4+T-bet+IFN-γ+ (Th1)-not CD4+GATA-3+IFN-γ+ (Th2) or CD4+CD25+FoxP3+ (Treg)-phenotypes, and not attributable to immune incompetence. When stratifying trastuzumab plus chemotherapy-treated patients by Th1 responsivity, Th1-nonresponsive patients demonstrated a worse DFS (median, 47 vs 113 months; P < .001) compared with Th1-responsive patients (hazard ratio, 16.9 [95% CI, 3.9-71.4]; P < .001). CONCLUSIONS AND RELEVANCE Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.

Efficacy of adjuvant chemotherapy for small bowel adenocarcinoma: A propensity score–matched analysis

The role of adjuvant chemotherapy (AC) in the treatment of small bowel adenocarcinoma is poorly defined. Previous analyses have been limited by small sample sizes and have failed to demonstrate a survival advantage.

Anti-HER2 CD4+ T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer

IntroductionA 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.MethodsAnti-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.ResultsDepressed 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.ConclusionsAnti-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.

Radiation as Immunomodulator: Implications for Dendritic Cell-Based Immunotherapy

The last decade has witnessed significant progress in the field of cancer immunotherapy. This has, in part, been driven by a growing recognition that elements of the innate immune response can be harnessed to induce robust immunity against tumor-associated targets. Nonetheless, as clinically effective immunotherapy for the majority of cancers remains a distant goal, attention has shifted toward multimodality approaches to cancer therapy, sometimes combining novel immunotherapeutics and conventional therapeutics. The traditional view of radiation therapy as immunosuppressive has been challenged, prompting a re-evaluation of its potential as an adjunct to, or even a component of immunotherapy. Radiation therapy may enhance expression of tumor-associated antigens, induce targeting of tumor stroma, diminish regulatory T-cell activity and activate effectors of innate immunity such as dendritic cells through Toll-like receptor (TLR)-dependent mechanisms. Here, we review recent progress in the field of dendritic cell-based immunotherapy, evidence for radiation-induced antitumor immunity and TLR signaling and the results of efforts to rationally integrate radiation into dendritic cell-based immunotherapy strategies.

Neoadjuvant therapy for gastric cancer: current evidence and future directions

Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies.

Implications of Lymph Node Staging on Selection of Adjuvant Therapy for Gastric Cancer in the United States: A Propensity Score-matched Analysis.

Objective:To compare the efficacy of adjuvant chemoradiotherapy (CRT) and chemotherapy alone (CA) in gastric adenocarcinoma patients undergoing gastrectomy in the United States (US). Background:A majority of US gastric adenocarcinoma patients are inadequately staged (<15 nodes examined). Despite this, and limited data comparing adjuvant CRT with CA in US patients, national guidelines endorse CA in selected patients undergoing D2 lymphadenectomy. Methods:Resected stage IB-III gastric adenocarcinoma patients receiving adjuvant CRT or CA (n = 3008) were identified in the National Cancer Database (1998–2006). Cox regression identified covariates associated with overall survival (OS). CRT and CA cohorts were matched (3:1) by propensity scores based on the likelihood of receiving CA. OS was compared by Kaplan-Meier estimates. Results:Adjuvant CA was associated with an increased risk of death (HR 1.29, P < 0.001) relative to CRT. Inadequate lymph node staging (LNS) and nodal positivity were strong predictors of risk-adjusted mortality (P < 0.001). After propensity score-matching, CRT demonstrated superior median OS compared with CA (36.1 vs 28.9 m; P < 0.0001), regardless of stage. CRT was superior to CA in inadequately staged patients (33.1 m vs 24.5 m; P < 0.001); this benefit was less pronounced with increasing nodal examination. CRT improved OS in node-positive disease (29.8 vs 22.2 m; P < 0.001), regardless of LNS adequacy. In node-negative disease, OS did not differ significantly between CRT and CA cohorts; however, node-negative patients undergoing inadequate LNS benefited from CRT. Conclusions:CRT is associated with improved stage-stratified OS compared with CA. Lymph node status and adequacy of surgical staging should influence adjuvant therapy selection in the United States.