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Sickle Cells Direct Cytotoxics And Oncolytic Virus To Hypoxic Tumor Niches And Induce A Tumoricidal Response

Sickle erythrocytes are a unique mammalian erythroid lineage that under hypoxic conditions alter their shape becoming rigid and adherent to blood vessels resulting in vaso-occlusion.  We reasoned that this property could make them useful for targeting and arresting the growth of oxygen-starved tumor cells. Such tumor cell niches constitute a major cause of resistance to treatment with chemotherapy and radiation.

Using hyperspectral imaging and intravital microscopy in a mouse model of triple negative breast cancer we showed that human sickle cells rapidly target hypoxic tumor niches wherein they formed microaggregates and shut down blood supply in more than 80% of tumor microvessels. Importantly, sickle cell infusions together with a pro-oxidant drug regimen significantly prolonged survival of tumor-bearing mice with minimal toxicity. In a clonogenic survival assay, we further showed that sickle cell-derived heme and oxidant surrogates induced profound tumor cells cytotoxicity (1).

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We subsequently showed that sickle cells containing osmotically captured cytotoxic drugs could be programmed ex vivo to deliver 4-fold more drug to hypoxic breast tumors than similarly treated normal erythrocytes. Likewise, sickle cells carrying oncolytic reovirus targeted and transferred the virus to tumor cells resulting in a significant tumoricidal response (2, 3). Hence, sickle cells can carry and deliver anti-cancer drugs and viruses into hypoxic tumors.

We reasoned that sickle cells unique ability to occlude tumor microvessels might explain why melanoma rarely occurs in patients with sickle cell anemia.  Indeed, we found that B16F10 melanoma implanted in sickle cell knockin mice with human SS hemoglobin showed minimal outgrowth relative to mice bearing human AA hemoglobin. Additional findings indicated that embryonic melanoma vascular sprouting is interdicted by the highly pro-oxidative/inflammatory vascular microenvironment in sickle cell mice. This latter constitutes a model milieu for the study of melanoma prophylaxis and pharmacologic mimicry (3).

We further showed that nucleic acids encoding cytotoxics perforin and granzyme or immune modulating superantigens SEG and SEI were cloned into the hemoglobin β-globin coding of a lentiviral vector downstream of an optimized Locus Control Region. Hematopoietic stem cells from humanized sickle cell mice were efficiently transduced with this vector and infused into irradiated hosts. The latter exhibited robust expression/function of the transgenic cytotoxics and superantigens in circulating sickle cells (4). Professor Mauro Magnini avers that the novelty of the approach is in the identity of a synergistic combination of the biological property of sickle erythrocytes (sickling of HbS in the hypoxic niche) with knowledge gained on regulatory sequences linked to the beta-globin gene (5).

In addition to treatment of hypoxic tumors, this technology could be adapted for surface expression of membrane cargo such as enzymes, receptors, transporters, chemokines and anti-autoimmune peptides.

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Collectively, these data indicate that sickle cells loaded or unloaded are useful in targeting hypoxic tumors where they aggregate and occlude tumor microvessels. They cooperate with exogenous pro-oxidants in a tumoricidal response and can carry and release oncolytic virus and drugs into hypoxic tumors. The highly pro-oxidative/inflammatory sickle cell microvascular environment can protect humanized sickle mice from developing melanoma. Sickle cells, therefore, are highly useful and versatile for treatment of hypoxic carcinoma and the sickle cell microenvironment is a model for the study of melanoma prevention.

References

  1. Terman DS, Viglianti BL, Zennadi R, Fels D, Boruta RJ, et al. (2013) Sickle Erythrocytes Target Cytotoxics to Hypoxic Tumor Microvessels and Potentiate a Tumoricidal Response. PLoS ONE 8(1): e52543. doi:10.1371/journal.pone.0052543.
  2. Choe SW, Terman DS, Rivers AE, Rivera J, Lottenberg R, Sorg BS Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery  Journal of Controlled Release 171 (2013) 184–192.
  3. Sun CW, Willmon C, Wu LC, Knopick P, Thoerner J, Vile R, Townes TM, Terman DS. Sickle Cells Abolish Melanoma Tumorigenesis in Hemoglobin SS Knockin Mice and Augment the Tumoricidal Effect of Oncolytic Virus In Vivo. Front Oncol. 2016 Jul 8;6:166. doi: 10.3389/fonc.2016.00166.
  4. Sun CW, Wu LC, Knopick PL, Bradley DS, Townes T, Terman DS Sickle cells produce functional immune modulators and cytotoxics. Am J Hematol. 2017 Oct;92(10):981-988. doi: 10.1002/ajh.24836.
  5. Magnini M.  Engineered red blood cells as therapeutic agents Engineered red blood cells as therapeutic agents. Am J Hematol. (2017) 92:979–980.

The study, Sickle cells produce functional immune modulators and cytotoxics was recently published in the American Journal of Hematology. This work was led by David S. Terman from the University of Alabama at Birmingham.

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