Predictors and benefits of multiagent chemotherapy for pancreatic adenocarcinoma: Timing matters.

INTRODUCTION: Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). METHODS: The National Cancer Database was queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. RESULTS: A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%; odds ratio [OR]: 0.59; p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18; 95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95% CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). CONCLUSION: Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy.

BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.

Divergent clinical outcomes in a phase 2B trial of the TLPLDC vaccine in preventing melanoma recurrence and the impact of dendritic cell collection methodology: a randomized clinical trial.

BACKGROUND: A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods. METHODS: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups. RESULTS: 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity. CONCLUSIONS: Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.

Immunologic and dose dependent effects of rapamycin and its evolving role in chemoprevention.

Rapamycin inhibits the mechanistic (formally mammalian) target of rapamycin (mTOR), an evolutionarily conserved intracellular kinase that influences activation of growth signaling pathways and immune responses to malignancy. Rapamycin has been found to have both immunosuppressant and immunostimulatory effects throughout the innate and adaptive responses based on the inhibition of mTOR signaling. While the immunosuppressant properties of rapamycin and mTOR inhibition explain rapamycin's success in the prevention of transplant rejection, the immunostimulatory characteristics are likely partially responsible for rapamycin's anti-neoplastic effects. The immunologic response to rapamycin is at least partially dependent on the dose and administration schedule, with lower doses inducing immunostimulation and intermittent dosing promoting immune function while limiting metabolic and immunosuppressant toxicities. In addition to its FDA-approved application in advanced malignancies, rapamycin may be effective as a chemopreventive agent, suspending progression of low-grade cancers, preventing invasive conversion of in situ malignancy, or delaying malignant transformation of established pre-malignant conditions.

Downstaging of Pancreatic Adenocarcinoma With Either Neoadjuvant Chemotherapy or Chemoradiotherapy Improves Survival.

BACKGROUND: Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. METHODS: The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio [HR] 0.82; 95 % confidence interval, 0.71-0.95; p = 0.01) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.

Maximizing Benefit of Virtual Learning: Lessons From the Coronavirus Disease 2019 Pandemic.

INTRODUCTION: The coronavirus disease 2019 pandemic has profoundly impacted surgical education. We assessed resident perceptions of our virtual academic program, which consists of daily lectures or case conferences held via a videoconferencing platform. METHODS: A survey evaluating attitudes and practices for virtual academics was administered to general surgery residents. A focus group was conducted to identify benefits, barriers to engagement, and opportunities for improvement for virtual education. A total of 19 residents completed the education survey, and seven residents participated in the focus group. RESULTS: While expressing preference toward in-person academics (84.2%), residents felt the virtual academics were of good quality (median rating 4/5) and preferred virtual academics to no academic sessions (94.7%). Of respondents, 57.9% believe that the coronavirus pandemic negatively impacted their surgical education. They believe their American Board of Surgery In-Training Examination preparation was not impacted. Residents preferred using a computer over a phone for academics (79% versus 16%). The focus group identified the benefits of virtual academics, including the ability to participate while away and having recordings available. Areas for improvement included reinforcement of protected time for academics, requiring cameras be on, increasing in-lecture polls, and creation of an online repository of recordings for review. Residents hoped a virtual component of academics and recordings would continue past the pandemic. CONCLUSIONS: Although virtual academics are not the preferred mode of learning in our residency, there are multiple unintended benefits. We recommend a hybrid academic model with in-person didactics and recorded video for later review.

Correlation of tumor microenvironment from biopsy and resection specimens in untreated colorectal cancer patients: a surprising lack of agreement.

BACKGROUND: Colorectal cancer (CRC) tumor microenvironment (TME) characteristics, such as tumor infiltrating lymphocyte (TIL) densities and PD-L1 status, are predictive of recurrence, disease-free survival, and overall survival. In many malignancies, TME characteristics are also predictive of response to immunotherapy. As window of opportunity studies using neoadjuvant immunotherapy become more common and treatment guidelines incorporate TME features, accurate assessment of the pre-treatment TME using the biopsy specimen is critical. However, no study has thoroughly evaluated the correlation between the TMEs of the biopsy and resection specimens. METHODS: We conducted a retrospective analysis of patients with stage I-III CRC with matched biopsy and resection specimens. CD3+, CD4+, CD8+, and FoxP3+ lymphocyte populations at the center of tumor (CT) and invasive margin (IM) and tumor PD-L1 status in the biopsy and resection specimens were evaluated. TIL populations were compared using Mann-Whitney U tests or Student's t tests and correlated using Pearson r. RESULTS: CD3+ and CD4+ densities were significantly higher in the CT of the biopsy relative to the resection specimen Comparing biopsy and resection specimens, no TIL population at either the CT or IM had a correlation coefficient > 0.5. Determining PD-L1 status based on biopsy tissue resulted in a sensitivity of 37.1%, specificity of 81.4%, and accuracy of 61.5%. CONCLUSIONS: These findings demonstrate significant discordance between the TME of the biopsy and resection specimens. Caution should be used when basing treatment decisions on pre-treatment endoscopic biopsy findings and when interpreting changes in the TME between pre-treatment biopsy and resection specimens after neoadjuvant therapy.

A Phase IIb Randomized Controlled Trial of the TLPLDC Vaccine as Adjuvant Therapy After Surgical Resection of Stage III/IV Melanoma: A Primary Analysis.

BACKGROUND: Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient's immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months). RESULTS: A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041). CONCLUSIONS: This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development. TRIAL REGISTRATION: NCT02301611.

Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39': An analysis of safety and immune response.

In this randomized phase Ib trial, we tested combining the E39 peptide vaccine with a vaccine created from E39', an attenuated version of E39. Patients with breast or ovarian cancer, who were disease-free after standard of care therapy, were enrolled and randomized to one of three arms. Arm EE received six E39 inoculations; arm EE' received three E39 inoculations followed by three E39'; and arm E'E received three E39' inoculations, followed by three E39. Within each arm, the first five patients received 500 µg of peptide and the remainder received 1000 µg. Patients were followed for toxicity, and immune responses were measured. This initial analysis after completion of the primary vaccination series has confirmed the safety of both vaccines. Immune analyses suggest incorporating the attenuated version of the peptide improves immune responses and that sequencing of E39 followed by E39' might produce the optimal immune response. TRIAL REGISTRATION: NCT02019524.

The development and use of the E75 (HER2 369-377) peptide vaccine.

E75 (nelipepimut-S) is an immunogenic peptide derived from the HER2 protein. When combined with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF), nelipepimut-S has been used as a vaccine that is capable of eliciting a robust anti-HER2 immune response. Early-phase clinical trials that enrolled women with node-positive or high-risk node-negative breast cancer who had been rendered disease free with standard of care therapy but were at risk for recurrence, demonstrated the vaccine to be safe with a suggestion of clinical benefit. Nelipepimut-S is currently being evaluated in a Phase III clinical trial. This article covers the preclinical and clinical development of nelipepimut-S.

Tumor lysate particle only vaccine (TLPO) vs. Tumor lysate particle-loaded, dendritic cell vaccine (TLPLDC) to prevent recurrence in resected stage III/IV melanoma patients: Results of a phase I/IIa trial.

BACKGROUND: The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine. METHODS: Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis. RESULTS: Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0 %, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7 %, p = 0.714) and OS (94.6% vs. 93.8 %, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw. CONCLUSIONS: In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial.

Prolonged Survival Following Intra-abdominal Mycobacterium abscessus Infection Without Antimicrobial Therapy or Surgical Intervention.

Management of Mycobacterium abscessus infection involves prolonged multidrug antibiotic therapy with surgical resection indicated in extensive disease and abscesses. We report a case of post-surgical intra-abdominal M. abscessus infection with prolonged survival and radiographic resolution without intervention. A 51-year-old female who had a prolonged hospital stay with multiple surgeries following a complicated laparoscopic sleeve gastrectomy developed multiple M. abscessus intra-abdominal and abdominal wall abscesses with cutaneous fistulae. She was started on a multidrug antibiotic regimen. However, the patient terminated the regimen after 4 weeks due to intolerable side effects and was transitioned to hospice care. She showed steady clinical improvement with radiographic resolution of the abscesses over the next year. In the context of the limited understanding of these infections, our finding is notable, given that in this period, she avoided potential hospitalizations, life altering side effects of prolonged antimicrobial therapy, and complications from more surgeries.

Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials.

Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach.

Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ.

NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.

Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

BACKGROUND: The authors conducted exploratory phase 1-2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3-restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). METHODS: These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3(+) ) expressing tumors. HLA-A2/A3(+) patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS: Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. CONCLUSIONS: The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.

Meeting the New Commission on Cancer Operative Standards: Where Do We Stand Now?

INTRODUCTION: The 2020 Commission on Cancer accreditation standards 5.7 and 5.8 address total mesorectal excision for rectal cancer and lymph node sampling for lung cancer. The purpose of this review was to assess our institution's compliance with these operative standards, which will be required in 2022 and 2023, and provide recommendations to other military training facilities seeking to comply with these standards. MATERIALS AND METHODS: A 2018-2020 single institution chart review was performed of operative and pathology reports. Identified deficits were addressed in meetings with colorectal and thoracic surgery leadership, and cases were followed to reassess compliance. RESULTS: A total of 12 rectal and 48 lung cancer cases met the inclusion criteria and were examined. Pre-intervention compliance for standards 5.7 and 5.8 was 58% and 35%, respectively, because of inadequate synoptic reporting and lymph node sampling. After intervention, compliance was 100%. CONCLUSIONS: Our institution requires changes to comply with new standards, including in areas of documentation and systematic pulmonary lymph node sampling. We provide lessons learned from our own institutional experience, including practical tips and recommendations to achieve compliance. All military training facilities performing lung and rectal oncologic resections should conduct an internal review of applicable cases in preparation for upcoming American College of Surgeons Commission on Cancer site visits.

Folate receptor α: a storied past and promising future in immunotherapy.

Folate receptor alpha (FR α) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR α is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR α are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR α to increase the immunogenicity of cancer or to generate active FR α-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR α and cover the various techniques designed to do this. Folate receptor alpha (FRα) is a unique tumor-associated antigen (TAA) with many characteristics that make it an attractive target for immunotherapy in cancer. Many different immunotherapeutic modalities utilizing FRα are being explored to treat cancer. The research is in various stages: some are just beyond conception, others have been tried and abandoned, and others still are progressing through human clinical trials. This review will cover immunotherapeutic methods, both active and passive, that target FRα.

Immunotherapy as a partner for HER2-directed therapies.

Introduction: Existing HER2-targeted therapies modulate the tumor microenvironment and the immunologic response cancer in a favorable way. While these therapies have made dramatic improvements in the treatment and prognosis of HER2-overexpressing malignancies, additional treatment options are still needed.Areas covered: This review covers the immunomodulatory effects of approved HER2-targeted therapies. We discuss the preclinical data that demonstrate an additive effect of the combination of trastuzumab or other HER2-targeting agents with immunomodulatory drugs. Finally, we report the initial studies on the combination of HER2-targeted agents together with immune checkpoint inhibitors or cancer vaccines in breast cancer.Expert opinion: Preclinical data suggest a synergistic effect of HER2-targeted therapy together with both checkpoint inhibitor and cancer vaccine immunotherapy. Results from initial trials with PD-1/PD-L1-blocking therapy together with HER2-targeted therapy have been negative, but responses were seen in patients with PD-L1+ breast cancer. Trastuzumab together with HER2-targeted cancer vaccination has shown benefits in triple negative breast cancer. Further trials are necessary and warranted to confirm the benefit of these combinations.