Immune responses and long‐term disease recurrence status after telomerase‐based dendritic cell immunotherapy in patients with acute myeloid leukemia

Khoury, H. Jean; Collins, Robert H.; Blum, William; Stiff, Patrick; Elias, Laurence; Lebkowski, Jane; Reddy, Anita; Nishimoto, Kevin; Sen, Debasish; Wirth, Edward D.; Case, Casey C.; DiPersio, John F.

doi:10.1002/cncr.30696

Cited by 73 publications

(57 citation statements)

References 45 publications

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“…This protein is highly upregulated in patients with AML, particularly those with poor risk cytogenetics. Khoury et al evaluated a DC vaccine, consisting of mature DCs transfected with mRNAencoding telomerase (hTERT) and LAMP, in AML patients [69]. Twenty-one patients in morphologic remission after prior therapy received a median number of 19 vaccinations with hTERT-DC (range: 3-32).…”

Section: Pr1 Vaccinesmentioning

confidence: 99%

Advances in Immunotherapy for Acute Myeloid Leukemia

2018

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Evasion of the host immune system is a key mechanism to promote malignant progression. Therapeutically targeting immune pathways has radically changed the treatment paradigm for solid and lymphoid tumors but has yet to be approved for myeloid malignancies. Here, we summarize the most recent advances in immunotherapy for acute myeloid leukemia. Topics reviewed here include adoptive cellular approaches (chimeric antigen receptor-T cells, natural killer and other immune cells), checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 and TIM-3) and vaccines (WT-1, HLA-A2 and hTERT). Emphasis is placed on agents with clear evidence of tumor-specific immune responses and/or clinical activity in early-phase trials. Despite concerns regarding heterogeneous antigen expression and cytokine release syndrome, immunotherapy remains a highly promising strategy for acute myeloid leukemia, particularly transplant-ineligible patients and minimal residual disease states.

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Section: Pr1 Vaccinesmentioning

confidence: 99%

Advances in Immunotherapy for Acute Myeloid Leukemia

2018

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“…Similarly, promising results were demonstrated in a clinical trial in which 22 AML patients in remission following chemotherapy were vaccinated with autologous DCs pulsed with human telomerase reverse transcriptase. 62 T-cell responses targeting t-HERT were observed in 58% of patients, and 58% of patients remained in remission with a median follow-up of 52 months. 62 We have developed a tumor vaccine in which patient-derived tumor cells are fused with autologous DCs such that a broad array of tumor antigens, including shared and neoantigens and those derived from the diverse clonal populations found in the primary tumor are presented in the context of DC-mediated costimulation.…”

Section: Whole Tumor Cells As a Source Of Vaccine Antigenmentioning

confidence: 99%

“…62 T-cell responses targeting t-HERT were observed in 58% of patients, and 58% of patients remained in remission with a median follow-up of 52 months. 62 We have developed a tumor vaccine in which patient-derived tumor cells are fused with autologous DCs such that a broad array of tumor antigens, including shared and neoantigens and those derived from the diverse clonal populations found in the primary tumor are presented in the context of DC-mediated costimulation. [63][64][65] In a phase 1 study, vaccination with patients with advanced myeloma (median of 4 prior regimens) was well tolerated with feasibility of the planned dose escalation to a dose of 4 3 10 6 fusion cells.…”

Section: Whole Tumor Cells As a Source Of Vaccine Antigenmentioning

confidence: 99%

Vaccine therapy in hematologic malignancies

Avigan

Rosenblatt

2018

Blood

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Immune-based therapy has emerged as a paradigm shift in cancer therapy with dramatic responses observed in previously incurable disease. Cancer vaccines are being developed to disrupt tumor-associated tolerance and activate and selectively expand tumor-specific lymphocytes within the native effector cell repertoire while maintaining immune-regulatory protection against autoimmunity. Although individual antigen approaches result in immune response with a suggestion of clinical effect in some settings, broader efficacy may be dependent on presentation of multiple antigens that capture clonal diversity presented in the context of functionally potent antigen-presenting cells. The use of whole cell-based strategies such as dendritic cell/tumor fusions have yielded provocative results in single-arm studies and are currently being explored in multicenter randomized trials. The posttransplant setting is a potentially promising platform for vaccination due to cytoreduction and relative depletion of inhibitory accessory cells fostering greater immune responsiveness. Integration of these efforts with other immunotherapeutic strategies and agents that target the tumor microenvironment is being studied in an effort to generate durable immunologic responses with clinically meaningful impact on disease.

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“…Immunological responses were observed, and 71% of the patients were still in CR at a median follow‐up of almost 5 years . Results of two major studies using monocyte‐derived DCs loaded with LAAs for post‐remission treatment of AML patients have been reported: vaccination with DCs electroporated with mRNA encoding hTERT resulted in antigen‐specific T‐cell responses in 11/19 patients; RFS after a median observation time of 52 months was 58% . Within a phase II trial, an anti‐leukaemic response was detected in 13/30 patients vaccinated with DCs loaded with wilms tumor 1 ( WT1 ) mRNA.…”

Section: Introductionmentioning

confidence: 99%

“…8 Results of two major studies using monocyte-derived DCs loaded with LAAs for post-remission treatment of AML patients have been reported: vaccination with DCs electroporated with mRNA encoding hTERT resulted in antigenspecific T-cell responses in 11/19 patients; RFS after a median observation time of 52 months was 58%. 9 Within a phase II trial, an antileukaemic response was detected in 13/30 patients vaccinated with DCs loaded with wilms tumor 1 (WT1) mRNA. A molecular remission defined by WT1 qPCR in the peripheral blood was achieved in 9/30 patients, and RFS and OS at 5 years were 30.8% and 50.0%, respectively.…”

Section: Introductionmentioning

confidence: 99%

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

et al. 2020

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Objectives Innovative post‐remission therapies are needed to eliminate residual AML cells. DC vaccination is a promising strategy to induce anti‐leukaemic immune responses. Methods We conducted a first‐in‐human phase I study using TLR7/8‐matured DCs transfected with RNA encoding the two AML‐associated antigens WT1 and PRAME as well as CMVpp65. AML patients in CR at high risk of relapse were vaccinated 10× over 26 weeks. Results Despite heavy pretreatment, DCs of sufficient number and quality were generated from a single leukapheresis in 11/12 cases, and 10 patients were vaccinated. Administration was safe and resulted in local inflammatory responses with dense T‐cell infiltration. In peripheral blood, increased antigen‐specific CD8+ T cells were seen for WT1 (2/10), PRAME (4/10) and CMVpp65 (9/10). For CMVpp65, increased CD4+ T cells were detected in 4/7 patients, and an antibody response was induced in 3/7 initially seronegative patients. Median OS was not reached after 1057 days; median RFS was 1084 days. A positive correlation was observed between clinical benefit and younger age as well as mounting of antigen‐specific immune responses. Conclusions Administration of TLR7/8‐matured DCs to AML patients in CR at high risk of relapse was feasible and safe and resulted in induction of antigen‐specific immune responses. Clinical benefit appeared to occur more likely in patients <65 and in patients mounting an immune response. Our observations need to be validated in a larger patient cohort. We hypothesise that TLR7/8 DC vaccination strategies should be combined with hypomethylating agents or checkpoint inhibition to augment immune responses. Trial registration The study was registered at https://clinicaltrials.gov on 17 October 2012 (NCT01734304) and at https://www.clinicaltrialsregister.eu (EudraCT‐Number 2010‐022446‐24) on 10 October 2013.

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Immune responses and long‐term disease recurrence status after telomerase‐based dendritic cell immunotherapy in patients with acute myeloid leukemia

Abstract: The generation of hTERT-DCs is feasible and vaccination with hTERT-DCs appears to be safe and may be associated with favorable recurrence-free survival. Cancer 2017;123:3061-72. © 2017 American Cancer Society.

Cited by 73 publications

References 45 publications

Advances in Immunotherapy for Acute Myeloid Leukemia

Advances in Immunotherapy for Acute Myeloid Leukemia

Vaccine therapy in hematologic malignancies

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

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