scholarly journals Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy

2021 ◽  
Vol 11 ◽  
Author(s):  
Hoyoung M. Maeng ◽  
Brittni N. Moore ◽  
Hadi Bagheri ◽  
Seth M. Steinberg ◽  
Jon Inglefield ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Dendritic Cell ◽  
Adverse Events ◽  
Phase I ◽  
Clinical Benefit ◽  
Metastatic Cancer ◽  
Objective Response ◽  
Definitive Treatment ◽  
Cell Vaccine ◽  
Dc Vaccine

BackgroundDespite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse.Patients and MethodsPart 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses.ResultsA total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4–124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%).ConclusionsThe AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.

Preliminary results of a phase I clinical trial using an autologous dendritic cell cancer vaccine targeting HER2 in patients with metastatic cancer or operated high-risk bladder cancer (NCT01730118).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2639-2639
Author(s):  
Hoyoung M. Maeng ◽  
Lauren Virginia Wood ◽  
Brittni Moore ◽  
Mohammadhadi H. Bagheri ◽  
Santhana Webb ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bladder Cancer ◽  
Dendritic Cell ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Cardiac Toxicity ◽  
Metastatic Cancer ◽  
Autologous Dendritic Cell ◽  
Dc Vaccine

2639 Background: We developed a HER2 targeting autologous dendritic cell (DC) vaccine transduced with an adenovirus expressing the extracellular and transmembrane domains of HER2 (AdHER2). In mice, the homologous vaccine cured virtually all mice with established or metastatic tumors. Protection was dependent on antibodies against HER2 that inhibited phosphorylation, but was ADCC independent. We translated these findings into a clinical trial. Methods: This is an open-label, phase I study in patients with 1) metastatic cancer that progressed after ≥ 1 standard therapies, or 2) history of high risk bladder cancer with definitive treatment, whose tumor is HER2 immunohistochemistry (IHC) score ≥ 1+ or FISH HER2/CEP17 ratio ≥ 1.8. Part 1 of the study enrolled patients naïve to HER2-directed therapies and Part 2 enrolled patients who progressed with ≥ 1 anti-HER2 therapy. Results: In Part 1, the lowest dose level (5E+6 viable DCs, N=7, 2 inevaluable) showed no benefit. At the second and third dose level (10E+6 and 20E+6; N=7 and N=4; 0 and 1 inevaluable in each), 1 CR (ovarian), 1 PR (stomach), and 3 SD (1 ovarian carcinosarcoma and 2 colon) were observed. Two bladder cancer patients who received vaccine as an adjuvant did not recur for +24 and +36 month each. In Part 2 (N=6, 2 inevaluable), 1 male breast cancer patient showed SD. Response assessed by Modified Immune Related Response Criteria is summarized in the Table. Injection-site reactions occurred in all patients and were self-limited. Echo, EKG and troponin follow up to 2 years showed no cardiac toxicity. Dose-expansion cohort (40E+6) is enrolling. Conclusions: We have translated a cancer vaccine from mice to a clinical trial. Preliminary results of a phase I trial of an autologous AdHER2 DC vaccine show potential clinical benefit in select patients with HER2 expressing tumors with no cardiac toxicity. Clinical trial information: NCT01730118. [Table: see text]

Portulaca oleracea L. polysaccharides enhance the immune efficacy of dendritic cell vaccine for breast cancer

2021 ◽  
Author(s):  
Guiyan Jia ◽  
Xingyue Shao ◽  
Rui Zhao ◽  
Tao Zhang ◽  
Xiechen Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dendritic Cell ◽  
Signaling Pathway ◽  
Mechanism Of Action ◽  
Dendritic Cell Vaccine ◽  
Portulaca Oleracea ◽  
Cell Vaccine ◽  
Dc Vaccine ◽  
Immune Efficacy ◽  
Dc Maturation

POL-P3b, as a promising dietary adjuvant for the DC vaccine of breast cancer, could induce DC maturation and the mechanism of action involved in the TLR4/MyD88/NF-κB signaling pathway.

scholarly journals Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhenyu Ding ◽  
Qing Li ◽  
Rui Zhang ◽  
Li Xie ◽  
Yang Shu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dendritic Cell ◽  
Cancer Treatment ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Therapeutic Modality ◽  
Advanced Lung Cancer ◽  
Cell Vaccine ◽  
Lung Cancer Treatment ◽  
Dc Vaccine

AbstractNeoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3–14 doses/person). In total, 12–30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1–2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

Dendritic cell vaccine modified by Ag85A gene enhances anti-tumor immunity against bladder cancer

2012 ◽  
Vol 14 (3) ◽  
pp. 252-260 ◽  
Author(s):  
Pei Zhang ◽  
Jinyan Wang ◽  
Danan Wang ◽  
Huan Wang ◽  
Fengping Shan ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Dendritic Cell ◽  
Tumor Immunity ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine

Phase I/II trial of pembrolizumab and cabozantinib in the treatment of metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4544-4544
Author(s):  
Elizabeth R Kessler ◽  
Junxiao Hu ◽  
Geetika Srivastava ◽  
Douglas Jerome Kemme ◽  
Praveena Iruku ◽  
...  
Keyword(s):  
Phase I ◽  
Primary Endpoint ◽  
Clinical Benefit ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Controlled Trial ◽  
Objective Response ◽  
Risk Category ◽  
Serious Adverse Events ◽  
Line Therapy

4544 Background: Checkpoint inhibitors (CPI) and vascular endothelial growth factor receptor inhibitors (VEGFi) are standard treatments for patients (pts) with mRCC. This phase I/II study evaluated the safety and efficacy of the novel combination of pembrolizumab (pembro) and cabozantinib (cabo). The phase I dose escalation data was presented at ASCO GU 2019. We now report the objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity of patients in the phase II dose expansion. Methods: Eligible pts had metastatic clear cell (ccRCC) or non-clear cell (nccRCC) histology, normal organ function, ECOG 0-1, and no prior exposure to pembro or cabo. Pts could be treatment-naïve or have received prior CPI and/or VEGFi. Pts were dosed at the recommended phase 2 dose of pembro 200 mg IV Q3W in combination with cabo 60 mg PO QD. Scans were obtained every 9 weeks. Treatment beyond progression, in the setting of continued clinical benefit, was allowed. The primary endpoint was ORR. Simon’s two-stage design was implemented to test the null hypothesis that ORR ≤ 0.20 versus the alternative that ORR ≥ 0.50. Results: Forty pts were enrolled, of which 34 pts (85%) had ccRCC and 6 pts (15%) had nccRCC. This was first-line treatment for 15 pts (38%) and second- and subsequent-line therapy for 25 pts (62%). IDMC risk category was favorable in 15%, intermediate in 72.5%, and poor in 12.5% of pts. Prior therapies included VEGFi in 17 pts (43%), CPI in 17 pts (43%), and 9 pts (23%) had both prior VEGFi and CPI in combination or sequentially. At a median follow up of 17.8 months (mo), the ORR was 60% (95% CI 0.458-1.00), clinical benefit rate (CBR) was 92.5% (95% CI 0.817-1.00), median time to response was 4.2 mo; median duration of response was 8.4 mo. Three of six nccRCC pts achieved partial response. Median PFS was 10.4 mo (95% CI 6.3 mo-NR). Median OS was not reached. Twelve patients remain on treatment. The most common grade 1 and 2 (G1/2) treatment-related AEs were diarrhea (53%), fatigue (49%), weight loss (47%), nausea (43%), and dysgeusia (43%). Twenty-five patients (47%) experienced a treatment-related G3 AE and there were no G4 related AEs. Thirteen pts experienced serious adverse events, 8 of which were related to treatment: G3 transaminitis and hypoglycemia were attributed to the combination; G3 pancreatitis, nephritis, and pneumonitis attributed to pembro; G3 pulmonary embolus, confusion due to reversible posterior leukoencephalopathy (RPLS), and stroke attributed to cabo. There was one treatment-related death in the pt with RPLS, possibly related to cabo. Conclusions: This study of the combination of pembrolizumab 200mg and cabozantinib 60mg met the primary endpoint of ORR. Benefit was seen in first- and subsequent-line therapy. The safety profile was manageable. This combination warrants further confirmation in a randomized controlled trial. Clinical trial information: NCT03149822.

scholarly journals Impact of concomitant medication use and immune-related adverse events on response to immune checkpoint inhibitors

Immunotherapy ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 141-149 ◽  
Author(s):  
Shipra Gandhi ◽  
Manu Pandey ◽  
Nischala Ammannagari ◽  
Chong Wang ◽  
Mark J Bucsek ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Benefit ◽  
Immune Checkpoint Inhibitors ◽  
Concomitant Medication ◽  
Checkpoint Inhibitors ◽  
Metastatic Cancer ◽  
Medication Use ◽  
Significant Difference ◽  
Β Blockers ◽  
The Impact

Aim: Patients receiving checkpoint inhibitors (CPI) are frequently on other medications for co-morbidities. We explored the impact of concomitant medication use on outcomes. Materials & methods: 210 metastatic cancer patients on CPI were identified and association between concomitant medication use and immune-related adverse events with clinical outcomes was determined. Results: Aspirin, metformin, β-blockers and statins were not shown to have any statistically significant difference on clinical benefit. 26.3% patients with clinical benefit developed rash versus 11.8% without clinical benefit (p < 0.05) on multivariate analysis. Conclusion: Use of common prescription and nonprescription medications in patients with multiple co-morbidities appears safe and does not have an adverse effect on CPI efficacy. The presence of rash predicted for a better response.

A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 263-263 ◽  
Author(s):  
Arlene O. Siefker-Radtke ◽  
Sijin Wen ◽  
Yu Shen ◽  
Kristi Stigall ◽  
David James McConkey ◽  
...  
Keyword(s):  
Phase I ◽  
Trial Design ◽  
Phase I Trial ◽  
Metastatic Cancer ◽  
Objective Response ◽  
Fixed Ratio ◽  
Single Component ◽  
Neutropenic Fever ◽  
Dose Finding ◽  
Poor Renal Function

263 Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase I design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.

Sign in / Sign up

Export Citation Format

Share Document