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Engineering Hematopoietic Stem Cells for a One-Two Punch of Cancer Immunotherapy

Mar 26, 2014 6:16:13 AM / by Maria

In Part I of this series we introduced T cell based immunotherapy and in Part II we discussed how chimeric antigen receptors (CARs) expressing T cells can be even more potent. In Part III below, we expand this concept further by covering hematopoetic stem cells and additional ways they can be engineered for promising immunotherapy of cancer and leukemia.

Hematopoietic stem cells (HSCs), found mostly in bone marrow, can generate all types of mature blood cells through proliferation and unique paths to differentiation. For over four decades, HSC transplants have been used as a source of stem cells that can produce necessary normal blood cells following chemotherapy or radiation, to restore marrow, or to treat genetic diseases of blood cells. HSCs can be obtained from bone marrow, peripheral blood, or umbilical cord blood, and HemaCare can provide many of these types of cells for research, including in the emerging field of cancer immunotherapy.

Hematopoietic Stem Cells for TCR- or CAR-mediated Immunotherapy

Hematopoietic stem cells can be engineered to express cancer antigen specific T cell receptors (TCRs) or chimeric antigen receptors (called CARs, as described in Part II) to bring a potentially continuous supply of targeted, anti-tumor T cells and other effectors like myeloid and natural killer (NK) cells. Several research groups have quite successfully transduced and transplanted human HSCs with prearranged TCRs that elicit an antigen-specific T cell response in mice [1]. The basis for the in vivo xenograph model used by Gschweng, et al begins with processing umbilical cord blood (UCB) or peripheral blood stem cells (PBSCs) to purify the CD34+ population enriched for hematopoietic stem cells, also available from HemaCare. The HSCs are then pre-stimulated before transduction with a lentiviral vector (encoding TCR or CAR of interest). The modified cells are transplanted via intra-hepatic (IH) injection to neonatal immune-deficient mice (NOD/SCID/IL2Rg−/− ) that have been preconditioned through irradiation (or other agents that have myeloablative or cytoreductive activity) and polychromatic flow cytometry can be used two months later for immunophenotypic analysis of peripheral blood (Figure 1).

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Hematopoietic stem cells with the introduction of anti-tumor TCRs or CARs have a lot of potential for cancer immunotherapy. They could provide ongoing, tireless anti-cancer activity because of their regenerative nature and ability to supply engineered effector T cells and T-lymphocyte progenitors, unlike T cells expanded ex vivo before infusion with a finite lifespan. Additionally, transplantation of HSCs engineered to have TCRs of interest avoids possible TCR mis-pairing with endogenous TCRs. Due to the mechanism and timing of allelic exclusion upstream of T cell development, this HSC approach establishes exclusive surface expression of the desired, antigen-targeted TCR.

Cell-based therapy is certainly promising and research in this area has the potential to change many lives, maybe even yours!

References:

[1] Gschweng, E., Oliveira, S., & Kohn, D. B. (2014). Hematopoietic stem cells for cancer immunotherapy. Immunological reviews, 257(1), 237-249.

Topics: PBCs, Cancer, Cell Therapy, Drug Discovery, leukemia, lymphoma, Peripheral blood cells, Stem Cell Therapy, Stem Cells, T Cells, Basic Research, Immunotherapy (Immunology)

Maria

Written by Maria

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