Register or Submit a manuscript.
Quick Link
OBM Genetics

(ISSN 2577-5790)

OBM Genetics is an international Open Access journal published quarterly online by LIDSEN Publishing Inc. It accepts papers addressing basic and medical aspects of genetics and epigenetics and also ethical, legal and social issues. Coverage includes clinical, developmental, diagnostic, evolutionary, genomic, mitochondrial, molecular, oncological, population and reproductive aspects. It publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). There is no restriction on the length of the papers and we encourage scientists to publish their results in as much detail as possible.

Publication Speed (median values for papers published in 2023): Submission to First Decision: 5.1 weeks; Submission to Acceptance: 17.0 weeks; Acceptance to Publication: 7 days (1-2 days of FREE language polishing included)

Current Issue: 2024  Archive: 2023 2022 2021 2020 2019 2018 2017
Open Access Communication

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

Kwang Poo Chang 1,*, Dennis K. P. Ng 2, Chia-Kwung Fan 3, Ramesh B. Batchu 4, Bala K. Kolli 1

  1. Department of Microbiology/Immunology, Center for Cancer cell Biology, Immunology and Infection, Chicago Medical School/Rosalindfranklin University of Medicine and Science, 3333 Green Bay Rd, N Chicago, IL 60064, USA

  2. Department of Chemistry, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong

  3. Department of Molecular Parasitology and Tropical Diseases, College of Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei, Taiwan

  4. Division of Surgical Oncology & Developmental, Therapeutics, The Michael and Marian Ilitch Department of Surgery, Wayne State University, 4646 John R Road, Detroit, MI 48201, USA

* Correspondence: Kwang Poo Chang

Academic Editor: Tapan K Bera

Special Issue: Molecular Cancer Therapeutics

Received: December 29, 2019 | Accepted: February 21, 2020 | Published: February 24, 2020

OBM Genetics 2020, Volume 4, Issue 1, doi:10.21926/obm.genet.2001103

Recommended citation:Chang KP, Ng DKP, Fan CK, Batchu RB, Kolli BK. Effective Delivery of Cancer Vaccines with Oxidatively Photo-Inactivated Transgenic Leishmania for Tumor Immunotherapy in Mouse Models. OBM Genetics 2020; 4(1): 103; doi:10.21926/obm.genet.2001103.

© 2020 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

The parasitic protozoa in the genus of Leishmania have exceptionally favorable attributes for exploitation as a vehicle for safe and effective delivery of transgenically incorporated vaccines against infectious and malignant diseases. A dual suicidal mechanism was installed in Leishmania via genetic and chemical engineering in vitro for accumulation of photosensitizers, rendering them sensitive to dim light for inactivation. Leishmania so inactivated are non-viable, but immunologically competent to deliver vaccines for immune-prophylaxis and –therapy. We have begun to explore the utility of these Leishmania for immunization against tumors in experimental mouse models.

Keywords

Leishmania; transgenics; photodyanmic inactivation; vaccine delivery; immunotherapy; tumor

Antigen-specific vaccination remains to be an option for tumor immunotherapy. Delivery of vaccines for this approach includes the strategies of using attenuated bacterial and viral constructs, e.g. Listeria [1,2] and Vaccinia [3]. Leishmania are parasitic protozoa, which are uniquely favorable for use as a universal platform to deliver vaccines for disease prevention and therapy [4,5]. Of particular interest are human cutaneous Leishmania, which causes innocuous, self-resolving skin infection [6]. Life-long immunity develops after its spontaneous cure, indicative of not only the presence of Leishmania-specific vaccine molecules against leishmaniasis but also adjuvanticity critical for effective vaccination against this and other diseases, e.g. malignancy. Leishmania are equipped with eukaryotic translational machineries and post-translational mechanisms for correct expression of multiple transgenic vaccines in abundance, thereby enabling them to serve as a carrier of high efficiency. Additionally, Leishmania are endowed with multifarious molecules to protect endogenous vaccines and target them specifically to antigen presenting cells (APC), i.e. dendritic cells (DC) and macrophages – the exclusive host cells for the residence of these parasites in natural infection. Attributable to these vaccine-protection and APC-homing properties are their surface lipoglycoconjugates, contributing to Leishmania adjuvanticity for effective vaccination. Leishmania are intrinsically safe. They produce no toxins [7,8] and show no human toxicity when used extensively after chemical or physical inactivation of whole cells in Leishmanin skin test for delayed type hypersensitivity and in several large scale vaccine trial attempts [6].

We have developed novel strategies to completely inactivate Leishmania to ascertain their safety with the preservation of its adjuvanticity as a vaccine carrier, viz. their genetic and chemical engineering in vitro to install light-activated duo suicidal mechanisms. This is made possible by partial genetic complementation of their deficiencies in heme biosynthetic enzymes for cytosolic accumulation of UV-sensitive uroporphyrin [9,10] and by loading of their endosomes exogenously with red-light sensitive cationic phthalocyanine [11,12,13]. Brief illumination of these photo-sensitized Leishmania results in their rapid oxidative inactivation initiated by the generation of extremely short-lived, albeit highly destructive singlet oxygen [14]. The safety and efficacy of such inactivated Leishmania have been demonstrated by immunization of animals, producing neither infection nor adverse effects [15], but prophylactically protect them against both cutaneous and visceral leishmaniasis [16,17], and immunotherapeutic activities clinically against drug-incurable canine leishmaniasis [18]. Moreover, Leishmania transgenically made to express ovalbumin (OVA) was shown to effectively deliver this antigen, after photodynamic inactivation, to DC for processing and presentation to activate OVA epitope-specific T cells in vitro [12]. Human cancer vaccine candidates have been successfully expressed in transgenic Leishmania, including enolase 1 (hENO1) [19]. These inactivated Leishmania produced impressive activities of immunotherapy by suppressing the emergence of tumors, which were pre-established with murine and human lung cancer cells in mice [20]. In one model, frozen samples of photo-inactivated Leishmania were used and found more effective than CpG ODN as adjuvants for immunizations with recombinant ENO1 peptides against murine tumor. In another, photo-inactivated hENO1-expressing Leishmania were used alone for immunizations of BALB/c mice followed by adaptive transfer of immunity via their splenic cells to immunocompromised mice bearing human tumor. Work is under way to assess such photodynamic vaccination in another murine model for pancreatic cancer. Of interest is to study the mechanism of adjuvanticity of photo-inactivated Leishmania in detail for comparison with other DAMP and PAMP adjuvants. Tumor antigens have been delivered to patients’ DC via conjugation with cell-penetrating peptides [21] and adeno-associated virus vectors [22] for ex vivo vaccination to activate CD8+ T cells for CTL activities of anti-tumor immunity. Such protocols are being developed for use with inactivated hENO1-Leishmania toward DC-based immunotherapy of human lung cancer.

Acknowledgments

Thanks are due to many colleagues for their indispensable collaboration and to the support of NIH-NIAID Grant # AI-68835, AI-7712375, AI097830 to KPC for the development of photodynamically inactivated Leishmania as vaccines and vaccine carriers.

Author Contributions

Conceptualization & writing, KP Chang; Funding Acquisition & Supervision, KP Chang, DKP Ng, RB Bachu, CK Fan; Methodology & Investigation, BK Kolli, RB Bachu, DKP Ng.

Competing Interests

The authors have declared that no competing interests exist.

References

  1. Hanson WG, Benanti EL, Lemmens EE, Liu W, Skoble J, Leong ML, et al. A potent and effective suicidal listeria vaccine platform. Infect Immun. 2019; 87: e00144-e00149. [CrossRef]
  2. Bolhassani A, Naderi N, Soleymani S. Prospects and progress of Listeria-based cancer vaccines. Expert Opin Biol Ther. 2017; 17: 1389-1400. [CrossRef]
  3. Prow NA, Jimenez Martinez R, Hayball JD, Howley PM, Suhrbier A. Poxvirus-based vector systems and the potential for multi-valent and multi-pathogen vaccines. Expert Rev Vaccines. 2018; 17: 925-934. [CrossRef]
  4. Chang KP, Kolli BK. New "light" for one-world approach toward safe and effective control of animal diseases and insect vectors from leishmaniac perspectives. Parasit Vectors. 2016; 9: 396. [CrossRef]
  5. Dutta S, Chang C, Kolli BK, Sassa S, Yousef M, Showe M, et al. Delta-aminolevulinate-induced host-parasite porphyric disparity for selective photolysis of transgenic Leishmania in the phagolysosomes of mononuclear phagocytes: A potential novel platform for vaccine delivery. Eukaryot Cell. 2012; 11: 430-441. [CrossRef]
  6. Chang KP. Overview of leishmaniasis with special emphasis on kala-azar in South Asia. In: Neglected tropical diseases, 2018 Eds. Sunit K. Singh, Springer, 1-63. [CrossRef]
  7. Chang KP, Reed SG, McGwire BS, Soong L. Leishmania model for microbial virulence: The relevance of parasite multiplication and pathoantigenicity. Acta Trop. 2003; 85: 375-390. [CrossRef]
  8. Chang KP, McGwire BS. Molecular determinants and regulation of Leishmania virulence. Kinetoplastid Biol Dis. 2002; 1: 1. [CrossRef]
  9. Sah JF, Ito H, Kolli BK, Peterson DA, Sassa S, Chang KP. Genetic rescue of Leishmania deficiency in porphyrin biosynthesis creates mutants suitable for analysis of cellular events in uroporphyria and for photodynamic therapy. J Biol Chem. 2002; 277: 14902-14909. [CrossRef]
  10. Dutta S, Furuyama K, Sassa S, Chang KP. Leishmania spp.: Delta-aminolevulinate-inducible neogenesis of porphyria by genetic complementation of incomplete heme biosynthesis pathway. Exp Parasitol. 2008; 118: 629-636. [CrossRef]
  11. Dutta S, Ray D, Kolli BK, Chang KP. Photodynamic sensitization of Leishmania amazonensis in both extracellular and intracellular stages with aluminum phthalocyanine chloride for photolysis in vitro. Antimicrob Agents Chemother. 2005; 49: 4474-4484. [CrossRef]
  12. Dutta S, Ongarora BG, Li H, Vicente Mda G, Kolli BK, Chang KP. Intracellular targeting specificity of novel phthalocyanines assessed in a host-parasite model for developing potential photodynamic medicine. PLoS One. 2011; 6: e20786. [CrossRef]
  13. Al-Qahtani A, Alkahtani S, Kolli B, Tripathi P, Dutta S, Al-Kahtane AA, et al. Aminophthalocyanine-mediated photodynamic inactivation of Leishmania tropica. Antimicrob Agents Chemother. 2016; 60: 2003-2011. [CrossRef]
  14. Dutta S, Kolli BK, Tang A, Sassa S, Chang KP. Transgenic Leishmania model for delta-aminolevulinate-inducible monospecific uroporphyria: Cytolytic phototoxicity initiated by singlet oxygen-mediated inactivation of proteins and its ablation by endosomal mobilization of cytosolic uroporphyrin. Eukaryot Cell. 2008; 7: 1146-1157. [CrossRef]
  15. Dutta S, Waki K, Chang KP. Combinational sensitization of Leishmania with uroporphyrin and aluminum phthalocyanine synergistically enhances their photodynamic inactivation in vitro and in vivo. Photochem Photobiol. 2012; 88: 620-625. [CrossRef]
  16. Kumari S, Samant M, Khare P, Misra P, Dutta S, Kolli BK, et al. Photodynamic vaccination of hamsters with inducible suicidal mutants of Leishmania amazonensis elicits immunity against visceral leishmaniasis. Eur J Immunol. 2009; 39: 178-191. [CrossRef]
  17. Viana SM, Celes FS, Ramirez L, Kolli B, Ng DKP, Chang KP, et al. Photodynamic vaccination of BALB/c mice for prophylaxis of cutaneous leishmaniasis caused by Leishmania amazonensis. Front Microbiol. 2018; 9: 165. [CrossRef]
  18. Manna L, Corso R. Section 3. Immunotherapy of canine leishmaniasis by photodynamic vaccination. In: Chang, KP et al. Progress toward development of photodynamic vaccination against infectious/malignant diseases and photodynamic mosquitocides, Proc. SPIE 10479, Light-Based Diagnosis and Treatment of Infectious Diseases, 1047912 (8 February 2018); doi: 10.1117/12.2281437; https://doi.org/10.1117/12.2281437. [CrossRef]
  19. Chang GC, Liu KJ, Hsieh CL, Hu TS, Charoenfuprasert S, Liu HK, et al. Identification of alpha-enolase as an autoantigen in lung cancer: Its overexpression is associated with clinical outcomes. Clin Cancer Res. 2006; 12: 5746-5754. [CrossRef]
  20. Shih, NY. Section 4. Immunotherapy of human and murine lung cancer by photodynamic vaccination in mouse models. In: Chang, KP et al. Progress toward development of photodynamic vaccination against infectious/malignant diseases and photodynamic mosquitocides, Proc. SPIE 10479, Light-Based Diagnosis and Treatment of Infectious Diseases, 1047912 (8 February 2018); https://doi.org/10.1117/12.2281437. [CrossRef]
  21. Batchu RB, Gruzdyn O, Potti RB, Weaver DW, Gruber SA. MAGE-A3 with cell-penetrating domain as an efficient therapeutic cancer vaccine. JAMA Surg. 2014; 149: 451-457. [CrossRef]
  22. Batchu RB, Gruzdyn OV, Moreno-Bost AM, Szmania S, Jayandharan G, Srivastava A, et al. Efficient lysis of epithelial ovarian cancer cells by MAGE-A3-induced cytotoxic T lymphocytes using rAAV-6 capsid mutant vector. Vaccine. 2014; 32: 938-943. [CrossRef]
Newsletter
Download PDF Download Citation
0 0
Newsletter  

TOP