Lentiviral vector followed by protein immunisation breaks tolerance against the self‐antigen Her1 and results in lung cancer immunotherapy

Alpízar, Yeranddy A.; Karwacz, Katarzyna; Arce, Frederick; Rivera, Arianna Yglesias; Fernández, Luis E.; Collins, Mary; Ramírez, Belinda Sánchez

doi:10.1002/jgm.2606

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…Heterologous prime-boost regimens that use two different vaccines to first prime the immune system and then boost its response have been shown to improve the efficacy of cancer vaccines in numerous preclinical animal models, and lentiviral vectors as the priming component have emerged as a promising new vaccine modality. [15][16][17][18][19] The priming component of CMB305 is LV305, which is a replication-incompetent, integration-deficient, improved third-generation lentiviral vector that contains RNA encoding for the full-length NY-ESO-1 protein. 20 Further, LV305 is based on the ZVex® platform, which has been shown to transduce dendritic cells through pseudotyping with an engineered Sindbis virus glycoprotein called SINVar1 that binds the C-type lectin receptor DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) expressed on immature dendritic cells.…”

Section: Introductionmentioning

confidence: 99%

A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1

et al. 2020

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Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-inhuman trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.

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Section: Introductionmentioning

confidence: 99%

A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1

et al. 2020

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“…This was dramatically demonstrated by the improved protection of nonhuman primates from simian immunodeficiency virus when a vaccinia-based vaccine was followed by a gp160 protein-based vaccine [38]. This concept has been illustrated in a variety of infectious models as well as a various murine tumor models where viral vectors, including LVs, were used to prime the immune system followed by protein boost [39–43]. While the reasons for the efficacy of heterologous prime-boost are still a matter of debate and are at least in part linked to inducing immune response against the vector in addition to the antigen, the order of the different vaccines used also appears to be important.…”

Section: Introductionmentioning

confidence: 99%

The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients

Pollack

2017

Expert Review of Vaccines

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Synovial Sarcoma (SS) and Myxoid Round Cell Liposarcoma (MRCL) are devastating sarcoma subtypes with few treatment options and poor outcomes in the advanced setting. However, both these diseases may be ideal for novel immunotherapies targeting the cancer-testis antigen, NY-ESO-1. Areas covered: In this review, we discuss the novel NY-ESO-1 targeted vaccine regimen, CMB305. This regimen uses a unique integration-deficient, dendritic-cell targeting lentiviral vector from the ZVex® platform, LV305, in order to prime NY-ESO-1 specific T cells. LV305 has single agent activity, and, in one case, caused a durable partial response in a refractory SS patient. CMB305 also includes a boost from a NY-ESO-1 protein vaccine given along with a potent toll-like-4 receptor agonist, glycopyranosyl lipid A. CMB305 induces NY-ESO-1 specific T cell responses in both SS and MRC patients and these patients had excellent overall survival (OS) outcomes in the initial phase I study. Expert commentary: CMB305 is a therapeutic vaccine regimen targeting NY-ESO-1 based on the lentiviral vaccine vector, LV305. Phase I studies have proven this vaccine is active immunologically. Data suggesting this vaccine may improve OS for SS and MRCL patients is exciting but early, and on-going work is testing the impact of CMB305 on patient outcomes.

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“…In a different experimental setting, mice immunized with the extracellular domain of the mEGFR developed a strong antibody response with high EGFR-antagonistic activity, which resulted in reduction of lung metastases (Ramírez et al, 2006, 2008). This anti-metastatic effect of the mEGFR vaccine also was abolished by in vivo depletion of the CD8+ T lymphocyte subpopulation (aguiar alpizar et al, 2012). Furthermore, it was demonstrated that an anti-EGFR antibody, but not a STKI, promotes an immunogenic cell death in a Lewis lung carcinoma model, involving induction of a CTL response in vivo (Garrido et al, 2011a).…”

Section: Egfr Oncogene Addiction May Reflect the Interconnection Of Smentioning

confidence: 99%

A view on EGFR-targeted therapies from the oncogene-addiction perspective

Pérez¹,

Crombet²,

León³

et al. 2013

Front. Pharmacol.

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Tumor cell growth and survival can often be impaired by inactivating a single oncogen– a phenomenon that has been called as “oncogene addiction.” It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. a critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the “EGFR addiction” phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

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Lentiviral vector followed by protein immunisation breaks tolerance against the self‐antigen Her1 and results in lung cancer immunotherapy

Abstract: The ability of this vaccine protocol to break both T cell and B cell tolerance to a self-antigen likely explains its effectiveness.

Cited by 5 publications

References 39 publications

A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1

A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1

The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients

A view on EGFR-targeted therapies from the oncogene-addiction perspective

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