Effective Delivery of Cancer Vaccines with Oxidatively Photo-Inactivated Transgenic Leishmania for Tumor Immunotherapy in Mouse Models

Chang, Kwang-Poo; Ng, Dennis K P; Fan, Chia-Kwung; Batchu, Ramesh B.; Kolli, Bala K.

doi:10.21926/obm.genet.2001103

Cited by 4 publications

(2 citation statements)

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“…Immunization of experimental mouse models with the vaccines delivered by 1 O 2 inactivated Leishmania produced encouraging preliminary results in two separate studies. One is the immunotherapeutic potential of the inactivated ENO1 transfectants [93]. Vaccination of BALB/c mice with these inactivated transfectants after implantation of murine ENO1-positive lung cancer cells prevented the development of otherwise massive tumors in their peritoneal cavity.…”

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confidence: 99%

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

et al. 2022

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“Bugs as drugs” in medicine encompasses the use of microbes to enhance the efficacy of vaccination, such as the delivery of vaccines by Leishmania—the protozoan etiological agent of leishmaniasis. This novel approach is appraised in light of the successful development of vaccines for Covid-19. All relevant aspects of this pandemic are summarized to provide the necessary framework in contrast to leishmaniasis. The presentation is in a side-by-side matching format with particular emphasis on vaccines. The comparative approach makes it possible to highlight the timeframe of the vaccine workflows condensed by the caveats of pandemic urgency and, at the same time, provides the background of Leishmania behind its use as a vaccine carrier. Previous studies in support of the latter are summarized as follows. Leishmaniasis confers life-long immunity on patients after cure, suggesting effective vaccination is achievable with whole-cell Leishmania. A new strategy was developed to inactivate these cells in vitro, rendering them non-viable, hence non-disease causing, albeit retaining their immunogenicity and adjuvanticity. This was achieved by installing a dual suicidal mechanism in Leishmania for singlet oxygen (1O2)-initiated inactivation. In vitro cultured Leishmania were genetically engineered for cytosolic accumulation of UV-sensitive uroporphyrin I and further loaded endosomally with a red light-sensitive cationic phthalocyanine. Exposing these doubly dye-loaded Leishmania to light triggers intracellular production of highly reactive but extremely short-lived 1O2, resulting in their rapid and complete inactivation. Immunization of susceptible animals with such inactivated Leishmania elicited immunity to protect them against experimental leishmaniasis. Significantly, the inactivated Leishmania was shown to effectively deliver transgenically add-on ovalbumin (OVA) to antigen-presenting cells (APC), wherein OVA epitopes were processed appropriately for presentation with MHC molecules to activate epitope-specific CD8+ T cells. Application of this approach to deliver cancer vaccine candidates, e.g., enolase-1, was shown to suppress tumor development in mouse models. A similar approach is predicted to elicit lasting immunity against infectious diseases, including complementation of the spike protein-based vaccines in use for COVID-19. This pandemic is devastating, but brings to light the necessity of considering many facets of the disease in developing vaccination programs. Closer collaboration is essential among those in diverse disciplinary areas to provide the roadmap toward greater success in the future. Highlighted herein are several specific issues of vaccinology and new approaches worthy of consideration due to the pandemic.

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confidence: 99%

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

et al. 2022

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“…We have been exploring inactivation of Leishmania via the principle of photodynamic therapy (PDT) as a strategy to render them non-viable for safe and effective use experimentally not only as whole-cell vaccines against leishmaniasis 12,13 but also as carriers for vaccines against other infectious and malignant diseases [14][15][16][17] . Photodynamic therapy makes use of dyes as photosensitizers (PS) that are excitable by light of specific wavelength to produce biocidal radicals, like singlet oxygen ( 1 O 2 ) and reactive oxygen species (ROS).…”

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Photodynamic inactivation of Leishmania braziliensis doubly sensitized with uroporphyrin and diamino-phthalocyanine activates effector functions of macrophages in vitro

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Viana

et al. 2020

Sci Rep

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Photodynamic inactivation of Leishmania has been shown to render them non-viable, but retain their immunological activities. Installation of dual photodynamic mechanisms ensures complete inactivation of species in the Leishmania subgenus, raising the prospect of their safe and effective application as whole-cell vaccines against leishmaniasis. Here, we report the successful extension of this approach to L. braziliensis in the Viannia subgenus, viz. genetic engineering of promastigotes for cytosolic accumulation of UV-sensitive uroporphyrin (URO) and their loading with red light excitable phthalocyanines (PC) that was cationized by chemical engineering. The transgenic strategy used previously produced L. braziliensis transfectants, which gave the same phenotype of aminolevulinate (ALA)-inducible uroporphyria as found in Leishmania subgenus, indicative of pre-subgenus evolutionary origin for similar genetic deficiencies in porphyrin/heme biosynthesis. In the present study, 12 independent clones were obtained and were invariably ALA-responsive, albeit to different extent for uroporphyrinogenesis and UV-inactivation. In a separate study, L. braziliensis was also found, like other Leishmania spp., to take up diamino-PC (PC2) for red light inactivation. In vitro interactions of a highly uroporphyrinogenic clone with primary macrophages were examined with the intervention of URO/PC2-medated double-photodynamic inactivation to ascertain its complete loss of viability. Doubly sensitized L. braziliensis transfectants were photo-inactivated before (Strategy #1) or after (Strategy #2) loading of macrophages. In both cases, macrophages were found to take up L. braziliensis and degrade them rapidly in contrast to live Leishmania infection. The effector functions of macrophages became upregulated following their loading with L. braziliensis photodynamically inactivated by both strategies, including CD86 expression, and IL6 and NO production. This was in contrast to the immunosuppressive infection of macrophages with live parasites, marked by IL10 production. The results provide evidence that photodynamically inactivated L. braziliensis are susceptible to the degradative pathway of macrophages with upregulation of immunity relevant cytokine and co-stimulatory markers. The relative merits of the two loading strategies with reference to previous experimental vaccination were discussed in light of the present findings with L. braziliensis.

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Leishmaniases

Chang¹

2021

Encyclopedia of Life Sciences

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Leishmaniases are neglected tropical diseases. The causative agents, Leishmania spp., are transmitted by the blood‐sucking female sand flies. The diseases are largely a zoonosis of canines, rodents and edentates. Humans are accidental dead‐end hosts, except in some places where human–human transmission is indicated by the absence of animal reservoirs. The diseases are present in >100 countries, mainly in tropical and subtropical areas, putting one billion world population at risk with an annual caseload of ∼one million and death in the tens of thousands. Leishmaniases are marked by a spectrum of clinical manifestations, ranging from self‐healing cutaneous lesions to facial mucocutaneous disfiguration to visceralisation with fatal consequence. Clinical managements of visceral leishmaniases rely on several toxic drugs with decreasing efficacy due to the development of drug resistance. Intraphagolysosomal parasitism of macrophages by these parasites is a key feature for considering molecular mechanisms of their virulence relevant to developing effective drugs and vaccines needed. Key Concepts The trypanosomatid protozoa in the genus of Leishmania cause leishmaniases. The diseases are neglected, but very widespread mainly in tropical and subtropical countries. The parasites live briefly in blood‐sucking sand flies and develop into infective promastigotes in the gut lumen. Infected sand flies transmit the parasites among animals, e.g. canines, rodents and edentates. Humans acquire leishmaniases from sand fly bites as a zoonosis with infected wild and domestic animals as the reservoirs. Human leishmaniasis is referred to as anthroponotic where reservoir animals have not been identified. The parasites live in the acidic endosomes/lysosomes of macrophages as amastigotes in the mammalian hosts. There are cutaneous, mucocutaneous and visceral leishmaniases. The spectrum of clinical manifestations results from immunopathology of different host‐parasite interactions. Life‐long immunity to leishmaniases often develops in patients cured of these diseases. Chemotherapy of leishmaniases relies on toxic drugs and loses its effectiveness to drug‐resistance. Visceral leishmaniasis has been brought under control in some endemic countries. Control programs include diagnosis of patients for treatments, surveillance of reservoirs and vectors for elimination. Lack of incentives for drug and vaccine development accounts for the persistence of leishmaniases.

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Effective Delivery of Cancer Vaccines with Oxidatively Photo-Inactivated Transgenic Leishmania for Tumor Immunotherapy in Mouse Models

Cited by 4 publications

References 21 publications

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

Photodynamic inactivation of Leishmania braziliensis doubly sensitized with uroporphyrin and diamino-phthalocyanine activates effector functions of macrophages in vitro

Leishmaniases

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