Clinical and Immunological Activity of WT1 Peptide Vaccination in Patients with Acute Myeloid Leukemia and Myelodysplasia: Results of a Phase II Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 567-567 ◽  
Author(s):  
Ulrich Keilholz ◽  
Anne Letsch ◽  
Antonia Busse ◽  
Anne M. Asemissen ◽  
Alexander Schmittel ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Tumor Antigens ◽  
Phase Ii Trial ◽  
Wilms Tumor ◽  
T Cell Response ◽  
Clinical Activity

Abstract The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, which are essential for tumor cell proliferation. WT1 is highly expressed in AML and in MDS upon appearance of blasts. A phase II trial of vaccination with the HLA-A2-restricted WT1.126–134 peptide was performed in patients with AML and MDS and overexpression of WT1 to determine immunogenicity and clinical activity. Patients received vaccinations with 0.2 mg WT1.126–134 peptide (day 3), 62.5 mcg dendritic cell-stimulating adjuvant GM-CSF (days 1–4) and 1 mg T helper protein keyhole limpet hemocyanin (day 3). The initial 13 patients were to receive 4 biweekly and subsequent 4-weekly vaccinations, the subsequent 13 patients were continuously vaccinated biweekly. Vaccination was continued in absence of overt disease progression. WT1 levels were assessed by quantitative RT-PCR and WT1-specific T cell responses by tetramer analyses and cytokine flow cytometry. Response assessment following IWG-MDS criteria was used, capturing stable disease and hematologic improvement. A duration of 8 weeks was required for stable disease. Enrolment was completed in June 2006 with 24 patients with AML and 2 with MDS (RAEB). Of the 24 AML patients, 16 had > 5% marrow blasts at study onset (8 without prior chemotherapy, 4 with disease persistence following chemotherapy, 4 with PR), and 8 were in CR at high risk for relapse. A median of 10 (range 4 – 23) vaccinations was administered with 8 patients currently still under treatment. No significant toxicity occurred. To date, 22 patients are evaluable for clinical response. Overall, 8/16 patients with > 5% marrow blasts at study onset displayed clinical efficacy of vaccine treatment (SD or better). One AML patient achieved CR for 12 months after brief initial progression, and 7 patients had disease stabilization (2, 2+, 3, 3, 6, 10+, 14 months). One of these patients with RAEBII had a major response of neutrophils and platelets, and one AML patient had initial progression and subsequent transient complete clearance of peripheral blasts. WT1 transcripts as molecular disease marker decreased at least 3-fold (range 3-fold - >50-fold, median >10-fold) in 12 of 20 currently evaluated patients, including all 8 patients with evidence of clinical efficacy and 4 of 5 AML patients vaccinated in CR. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 12 of 16 evaluated patients including all 6 of these 16 patients with evidence for clinical efficacy. This study shows that WT1 vaccination has promising antileukemia activity. A multicenter comparative WT1 vaccination study in CR patients at high risk of relapse is currently initiated.

Clinical and immune responses of WT1-peptide vaccination in patients with acute myeloid leukemia

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2511-2511 ◽  
Author(s):  
U. Keilholz ◽  
A. Letsch ◽  
A. Asemissen ◽  
W. Hofmann ◽  
L. Uharek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Intracellular Cytokine Staining ◽  
T Cell Response ◽  
Antileukemic Activity ◽  
Acute Myeloid

2511 Background: The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation. WT1 is highly expressed both in myeloid leukemias and many carcinomas. This phase 2 proof-of-concept trial was initiated to determine immunogenicity and toxicity of vaccination with a novel HLA-A2-restricted WT1 peptide vaccine. Methods: Sixteen HLA-A2-positive patients with acute myeloid leukemia and one patient with myelodysplasia received 3–18 vaccinations (median 8) of WT1. 126–134 peptide (0.2 mg) together with the T helper protein keyhole limpet hemocyanin (1 mg) and in addition GM-CSF (75 mcg for four days) and. Twelve patients had elevated blast counts at study entry and 5 patients complete remission with high risk for relapse. Results: Six of 12 patients with presence of leukemic blasts had evidence of antileukemic activity. One patient achieved complete remission for 12 months. The patient with myelodysplasia RAEB II had a major response of neutrophils and platelets. Two patients had minor responses with transient clearance of peripheral blasts or improvement of hematopoiesis, and two patients achieved disease stabilization for 3 and 14 months. WT1 transcripts as molecular disease marker decreased in 5 of these 6 patients and also in 4 of 5 high-risk patients. No significant toxicity occurred. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 9 of 13 patients by tetramer analysis and 8 of 13 patients by intracellular cytokine staining. Conclusion: These results show that WT1 vaccination can induce functional T cell responses associated with antileukemic activity and warrant trials of WT1 vaccination in patients at high risk of relapse and with WT1-expressing carcinomas. No significant financial relationships to disclose.

Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (36) ◽  
pp. 4134-4140 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Gökbuget ◽  
Gerhard Zugmaier ◽  
Petra Klappers ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Hematopoietic Stem ◽  
Dismal Prognosis ◽  
Bispecific T Cell Engager

Purpose Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. Patients and Methods Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). Results Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. Conclusion The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.

Safety and preliminary immunogenicity of JNJ-64041809, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy, in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16509-e16509
Author(s):  
Charles G. Drake ◽  
Russell Kent Pachynski ◽  
Sumit Kumar Subudhi ◽  
Douglas G. McNeel ◽  
Emmanuel S. Antonarakis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Antigens ◽  
Phase 1 ◽  
Blood Cultures ◽  
T Cell Response ◽  
Clinical Activity ◽  
Grade 3

e16509 Background: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live attenuated, double-deleted Listeria monocytogenes (LADD- Lm)-based immunotherapy targeting relevant prostate cancer antigens, was evaluated in a phase 1, multicenter, open-label study in patients (pts) with mCRPC. Methods: Men aged ≥18 years with progressive mCRPC who had received ≥2 prior approved therapies were included. The recommended phase 2 dose (RP2D) and the safety and immunogenicity of JNJ-809 were evaluated. Dose-limiting toxicities (DLTs), adverse events (AEs), T cell response, tumor response, and JNJ-809 bacterial shedding profile were assessed at 2 dose levels, 1 x 108 and 1 x 109 colony forming units (CFU). Results: 26 pts (median age 66.5 years, White 96%) were enrolled (1 x 108 CFU, n = 6; 1 x 109 CFU, n = 20). Median duration of treatment was 2.5 months (range 0-9.7). No DLTs occurred and 1 x 109 CFU was selected as the RP2D. Most common AEs were chills (n = 24, 92%), pyrexia (n = 21, 81%), and fatigue (n = 16, 62%). Grade ≥3 AEs were reported in 18 (69%) pts and serious AEs in 7 (27%) pts including 1 pt with investigator-assessed treatment-related grade 3 intestinal obstruction. At 1 x 108 CFU, all pts had negative blood cultures. At 1 x 109 CFU, 6 pts had LADD- Lm-positive blood cultures on day 1; blood cultures on all subsequent days were negative. JNJ-809 transiently induced peripheral cytokines including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of 7 evaluable pts (1 x 109 CFU), post-treatment T cell responses were demonstrated in 6 pts to the Listeria antigen LLO and in 5 pts to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease (SD) in 13/25 evaluable pts with SD ≥16 weeks in 4 pts. The study was terminated early as the data collected from 26 pts were considered sufficient to evaluate safety and immune responses. Conclusions: JNJ-809 has a manageable safety profile consistent with that of other LADD- Lm-based therapies. Observed activation of immune responses with monotherapy did not translate into clinical activity, and further development of JNJ-809 will likely require a combination approach. Clinical trial information: NCT02625857.

A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Phase Ii Trial ◽  
Ex Vivo ◽  
Vaccine Strategy ◽  
Randomized Phase Ii

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

scholarly journals Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Paola Di Giacinto ◽  
Francesca Rota ◽  
Laura Rizza ◽  
Davide Campana ◽  
Andrea Isidori ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Chromogranin A ◽  
Carcinoid Syndrome ◽  
Phase Ii Trial ◽  
Randomized Study ◽  
Clinical Aspects ◽  
Clinical Activity ◽  
Octreotide Lar ◽  
Well Differentiated

Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy.

Saci-IO HR+: Randomized phase II trial of sacituzumab govitecan (SG) +/- pembrolizumab in PD-L1+ hormone receptor-positive (HR+) / HER2- metastatic breast cancer (MBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1102-TPS1102
Author(s):  
Ana Christina Garrido-Castro ◽  
Tanya Elizabeth Keenan ◽  
Tianyu Li ◽  
Paulina Lange ◽  
Catherine Callahan ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Immune Cell ◽  
Phase Ii Trial ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Cytotoxic T Cell ◽  
Antibody Drug Conjugate ◽  
Randomized Phase Ii ◽  
Treatment Research

TPS1102 Background: Immune checkpoint inhibitors (ICIs) have not yet benefited most patients with MBC. In HR+ MBC, the first randomized trial combining an ICI with chemotherapy demonstrated no clinical benefit with the addition of pembrolizumab to eribulin.1 The optimal ICI combination agent to overcome primary resistance in HR+ MBC is unknown. One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.5 months in HR+ MBC refractory to endocrine therapy.2 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity.3 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models.4 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors,5 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors. Methods: This is a multi-center 1:1 randomized phase II trial to investigate whether the addition of pembrolizumab (200 mg IV every 3 weeks) to SG (10 mg/kg IV days 1+8 every 21 days) improves PFS compared to SG alone in HR+ HER2- MBC that is PD-L1+ by central assessment with 22C3 combined positive score (CPS) ≥ 1 (NCT04448886). Key eligibility criteria include at least 1 prior hormonal therapy and no more than 1 prior chemotherapy for HR+ MBC. Eligible patients must have evaluable disease, and previously treated brain metastases are permitted. Exclusion criteria include prior treatment with SG, irinotecan, and PD-1/L1 inhibitors. Based on a sample size of 110 patients, the trial has 80% power to detect a 3-month difference in median PFS from 5.5 months in the SG-alone cohort to 8.5 months in the SG + pembrolizumab cohort with a one-sided alpha of 0.1. Participants undergo mandatory baseline and on-treatment research biopsies if their disease is safely accessible. Tumor biopsies will be evaluated for Trop-2, immune cells, inhibitory checkpoints, transcriptomic signatures, and genomic alterations. Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed. The trial is currently open and enrolling patients. References: 1) Tolaney SM et al. JAMA Oncol 6, 1598-1605 (2020). 2) Kalinksy K et al. Ann Oncol 12, 1709-1718 (2020). 3) Cardillo TM et al. Bioconjug Chem 26, 919-931 (2015). 4) Iwai T et al. Oncotarget 9, 31411-31421 (2018). 5) Hibino S et al. Cancer Res 78, 3027-3040 (2018). Clinical trial information: NCT04448886 .

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