Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Part I. Stem Cells
The clinical use of HSCs continues to improve and expand. Current limitations include the toxicity of preconditioning, GVHD for allogeneic transplants, contaminating cancer cells for autologous transplants and graft failure due to insufficient cells. Mostly outside of the scope of this overview, treatment of the underlying cancer is another limitation. Some areas in which improvements can be expected include the preconditioning of the patient, the purity of the stem cell graft, the addition of defined cells to the stem cell graft and, potentially, the origin of the HSCs used. These developments will also help expand the use of HSCs beyond current indications, which are still mostly focused on the treatment of cancer.
The morbidity and mortality associated with HSC transplantation have been reduced through many modifications. The development of reduced intensity conditioning regimens (so-called ‘minitransplants’) has been very important in reducing transplant-related complications. Graft-versus-host activity is both good and bad in the treatment of cancer. The response against the host cancer cells (GVL) can be decisive in achieving a cure. However, the uncontrolled rejection of healthy host tissue can be life threatening. In treating conditions other than cancer, the rejection of host tissue in GVHD is bad and not acceptable. The stem cell source and preconditioning can help reduce the incidence. The use of purified HSCs (without any contaminating T cells) can completely prevent GVHD, but these require higher cell doses to ensure engraftment. Adjuvant populations such as facilitator cells can help engraftment without increasing the risk of GVHD. Other cells can be used to reduce the incidence of infections in the (immediate) post-transplant period. For example, myeloid progenitor cells, which can be cryopreserved and used without matching, provide rapid and mostly transient engraftment with myeloid cells that can protect from fungal and bacterial infections (Arber et al., 2005). They are currently undergoing clinical trials (Cellerant Therapeutics, 2012). While enormous progress has been made in reducing the toxic effects of preconditioning, further improvements may well be possible. More targeted therapy can use antibodies to prepare the host to receive a stem cell graft. Preclinical studies have indicated that antibodies blocking c-Kit can be used to eliminate HSCs and prepare a host for transplant (Czechowicz et al., 2007), based on the fact that HSCs are dependent on two signals for survival: one involving the Bcl-2 pathway and one involving signalling through c-Kit (Domen and Weissman, 2000). Combined with antibodies or small molecules targeting specific immune cells, this could be one path towards designing a targeted approach with limited toxicity. Additional approaches to this end may arise from ongoing work on defining factors involved in stem cell specification and interaction (Clements and Traver, 2013; Leatherman, 2013).
A final piece of the puzzle – the ability to generate stem cells – is also changing rapidly (Figure 4.3). Classically, HSCs are harvested from the bone marrow, either directly, after mobilization into circulation or from UCB. While extremely successful, this approach has limitations. Most importantly, the stem cell numbers that can be obtained are limited and, in autologous harvests, often contaminated. One of the most exciting developments in stem cell biology in the last decade has been the discovery that a pluripotent stem cell phenotype can be induced in many different types of somatic cells following transduction with a limited set of genes (Takahashi et al., 2007; Yu et al., 2007). These so-called ‘induced pluripotent stem cells’ (iPSCs) are of obvious interest, as they can be patient-specific and have the potential to differentiate into many different lineages. The transduction process, however, raises questions about potential long-term risks, especially in therapeutic settings. Reprogramming of cells from one fate to another without their passing through a pluripotent intermediary (e.g. fibroblasts into neurons) has also been demonstrated recently (Chambers and Studer, 2011). While it is in early stages, this approach may open additional avenues to obtaining genetically defined cells for research and therapy. The recent observation that it is possible to reprogramme somatic cells into pluripotent stem cells simply by stressing them through incubation in a mild acid environment for 30 minutes (STAP protocol) (Obokata et al., 2014), provided it can be confirmed, opens up what may be the most exciting novel method for obtaining cells, including HSCs, for clinical use, as it does not require transfection. If the potential suggested by these initial reports can be realized – something that will require a lot of additional work – it may in the long term transform many of the aspects of the therapeutic use of HSCs and other stem cells discussed in this chapter.
Figure 4.3. Current and potential future sources of HSCs for clinical use. (A) Currently, HSCs are harvested directly from the donor, in the form of either bone marrow or blood (as pheresed mobilized peripheral blood in adults or UCB at birth). The preparation can undergo limited manipulation, such as enrichment for CD34+ cells. Some of the major limitations are the number of cells that can be obtained, the presence of alloreactive lymphocytes in allogeneic preparations and the presence of cancer cells in autologous preparations. (B) Going forward, it may become possible to harvest somatic cells (possibly blood cells) from the donor, and either to derive pluripotent cells through transfection or stress treatment, expand these and rederive committed HSCs, or, possibly, if conditions can be defined, to directly reprogramme the harvested somatic cells into HSCs. The HSCs can then be administered to the recipient or can be used to derive specific adjuvant populations, such as myeloid progenitor cells. Other adjuvant populations, such as lymphocytes, may be harvested directly from the donor. The pluripotent cell phase will allow for manipulations such as gene therapy, and the expansion at this stage may go a long way towards ensuring a sufficient numbers of cells. HSCs derived through this process should be free of host reactive lymphocytes and contaminating cancer cells. Due to the expansion step, it may eventually be possible to bank these cells based on haplotype.