Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma

Lowe, Devin B.; Bose, Anamika; Taylor, Jennifer L.; Tawbi, Hussein Abdul-Hassan; Lin, Yan; Kirkwood, John M.; Storkus, Walter J.

doi:10.4161/onci.27589

Cited by 39 publications

(53 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human tumors, especially recurrent GBM, are complex mixtures of cells, including malignant cancer cells, inflammatory cells including myeloidderived suppressor cells (MDSCs) and lymphocytes, 56,57 nontransformed cellular matrix, necrotic centers, and acellular fibrotic tracts from previous therapies. 58 As noted above, in these clinical circumstances it is unlikely that 100% tumor cell transduction can be achieved, and some form of bystander effect that leads to death of uninfected cells may be necessary for the best clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

Twitty

DiagoOscar

HoganDaniel

et al. 2016

Human Gene Therapy Methods

View full text Add to dashboard Cite

Toca 511 is a modified retroviral replicating vector based on Moloney c-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD 50 values between 0.02 and 6 lg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD 50 . The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals.INTRODUCTION THE IDEA OF USING replication-competent viruses as a direct therapy for the treatment of cancer emerged more than a century ago.1 The c-retrovirus murine leukemia virus (MLV) is an attractive tool for tumor gene therapy, as its nonlytic life cycle and requirement for host cell division allow for tumor-selective enhanced gene transfer 2 and spread throughout the tumor. This MLV-based approach to gene therapy has been used to deliver and express the cytosine deaminase (CD) gene into tumor cells, providing a specific conversion of the well-tolerated antifungal prodrug, 5-fluorocytosine (5-FC), into the potent chemotherapeutic 5-fluorouracil (5-FU), which has been well established in preclinical studies. [2][3][4][5][6] Building on this concept, Tocagen's retroviral replicating vector (RRV) named Toca 511 7 (vocimagene amiretrorepvec) preferentially infects tumors without immediate cell killing and encodes an optimized yeast cytosine deaminase (yCD) that converts 5-FC into 5-FU within infected tumors. 3,4,7,8 We are currently investigating the clinical utility, in recurrent high-grade glioma, of Toca 511 in combination with Toca FC, an investigational orally administered extended-release formulation of 5-FC (NCT01470794, NCT01156584, NCT01985256, and NCT02414165).CD is lacking or poorly expressed in most human cells but is often expressed in yeast and bacteria as part of the pyrimidine salvage pathway and is responsible for converting cytosine to uracil and ammonia. CD also catalyzes, by means of a deamination step, the conversion of the prodrug 5-FC to the chemotherapeutic drug 5-FU 9,10 within cancer cells expressing gene therapy-delivered CD. CDbased prodru...

show abstract

Section: Discussionmentioning

confidence: 99%

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

Twitty

DiagoOscar

HoganDaniel

et al. 2016

Human Gene Therapy Methods

View full text Add to dashboard Cite

show abstract

“…44 This situation may be remedied by combined administration of anti-angiogenic agents (such as the TKIs axitinib, dasatinib or sunitinib) along with a tumor-specific vaccine. [45][46][47] Our DLK1/DLK2-targeted vaccine has an advantage over conventional TAA-targeted vaccine due to the proximal accessibility of circulating T effector cells to tumor-associated vascular pericyte targets in contrast to tumor cells that require T cells to enter, transmigrate and functionally persist within the TME to mediate meaningful therapeutic action. Furthermore, our vaccine promotes sustainable immune-mediated VN that would be envisioned to improve the deliverability of codelivered chemotherapies or adoptively-transferred (TCR-or CAR-engineered) T cells, theoretically without invoking the development of drug resistance or the adverse side-effects associated with anti-VEGF monoclonal antibodies and TKIs.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

View full text Add to dashboard Cite

When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

show abstract

“…Low dose oral dasatinib in combination with anti-melanoma DC-vaccine significantly increased tumor infiltrating CTL and CD11c C DC, decreased signaling through hypoxia mediated pathways, increased intratumoral expression of pro-inflammatory cytokines and chemokines, and resulted in a striking decrease in tumor growth. 69 Taken as a group these studies show that concomitant modulation of immunosuppressive pathways may enhance DC-mediated anti-tumor immune response.…”

Section: Concomitant Immunomodulationmentioning

confidence: 97%

Dendritic cell vaccines: A review of recent developments and their potential pediatric application

Elster

Krishnadas

Lucas

2016

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

For many cancers the use of conventional chemotherapy has been maximized, and further intensification of chemotherapy generally results in excess toxicity with little long-term benefit for cure. Many tumors become resistant to chemotherapy, making the investigation of novel approaches such as immunotherapy of interest. Because the tumor microenvironment is known to promote immune tolerance and down regulate the body's natural defense mechanisms, modulating the immune system with the use of dendritic cell (DC) therapy is an attractive approach. Thousands of patients with diverse tumor types have been treated with DC vaccines. While antigen specific immune responses have been reported, the duration and magnitude of these responses are typically weak, and objective clinical responses have been limited. DC vaccine generation and administration is a multi-step process with opportunities for improvement in source of DC for vaccine, selection of target antigen, and boosting effector cell response via administration of vaccine adjuvant or concomitant pharmacologic immunomodulation. In this review we will discuss recent developments in each of these areas and highlight elements that could be moved into pediatric clinical trials.

show abstract

Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma

Cited by 39 publications

References 49 publications

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Dendritic cell vaccines: A review of recent developments and their potential pediatric application

Contact Info

Product

Resources

About