A Patient’s Own Bone Marrow Stem Cells Defeat Drug-Resistant Tuberculosis

People infected with multidrug-resistant forms of tuberculosis could, potentially, be treated with stem cells from their own bone marrow. Even though this treatment is in the early stage of its development, the results of an early-stage trial of the technique show immense promise.

British and Swedish scientists have tested this procedure, which could introduce a new treatment strategy for the estimated 450,000 people worldwide who have multi drug-resistant (MDR) or extensively drug-resistant (XDR) TB.

This study, which was published in the medical journal, The Lancet, showed that over half of 30 drug-resistant TB patients treated with a transfusion of their own bone marrow stem cells were cured of the disease after six months.

“The results … show that the current challenges and difficulties of treating MDR-TB are not insurmountable, and they bring a unique opportunity with a fresh solution to treat hundreds of thousands of people who die unnecessarily,” said TB expert Alimuddin Zumla at University College London, who co-led the study.

TB initially infects the lungs but can rapidly spread from one person to another through coughing and sneezing. Despite its modern-day resurgence, TB is often regarded as a disease of the past. However, recently, drug-resistant strains of Mycobacterium tuberculosis, the microorganism that causes TB, have spread globally, rendering standard anti-TB drug treatments obsolete.

The World Health Organisation (WHO) estimates that in Eastern Europe, Asia and South Africa 450,000 people have MDR-TB, and close to half of these cases will fail to respond to existing treatments.

Mycobacterium tuberculosis, otherwise known as the “tubercle bacillus, trigger a characteristic inflammatory response (granulomatous response) in the surrounding lung tissue that elicits tissue damage (caseation necrosis).

Bone-marrow stem cells are known to migrate to areas of lung injury and inflammation. Upon arrival, they initiate the repair of damaged tissues. Since bone marrow stem cells also they also modify the body’s immune response, they can augment the clearance of tubercle bacilli from the body. Therefore, Zumla and his colleague, Markus Maeurer from Stockholm’s Karolinska University Hospital, wanted to test bone marrow stem cell infusions in patients with MDR-TB.

In a phase 1 trial, 30 patients with either MDR or XDR TB aged between 21 and 65 who were receiving standard TB antibiotic treatment were also given an infusion of around 10 million of their own bone marrow-derived stem cells.

The cells were obtained from the patient’s own bone marrow by means of a bone marrow aspiration, and then grown into large numbers in the laboratory before being re-transfused into the same patient.

During six months of follow-up, Zumla and his team found that the infusion treatment was generally safe and well tolerated, and no serious side effects were observed. The most common non-serious side effects were high cholesterol levels, nausea, low white blood cell counts and diarrhea.

Although a phase 1 trial is primarily designed only to test a treatment’s safety, the scientists said further analyses of the results showed that 16 patients treated with stem cells were deemed cured at 18 months compared with only five of 30 TB patients not treated with their own stem cells.

Maeurer stressed that further trials with more patients and longer follow-up were needed to better establish how safe and effective the stem cell treatment was.

But if future tests were successful, he said, this could become a viable extra new treatment for patients with MDR-TB who do not respond to conventional drug treatment or for those patients with severe lung damage.

Preventing the Rejection of Embryonic Stem Cell Derivatives – Take Two

Yesterday I blogged about the paper from Yang Xu’s group that used genetically engineered embryonic stem cells to make adult cell types that were not rejected by the immune systems of mice with humanized immune systems. I would like to say a bit more about this paper before I leave it be.

First of all, Xu and his colleagues engineered the cells to express the cell-surface protein PD-L1, which stands for programmed cell death ligand 1 (also known as CD274), and another protein called CTLA4-Ig. The combination of these two proteins tends to make these cells invisible to the immune system for all practical intents and purposes.

PD-L1, however, is used by tumor cells to evade detection by the immune system. For example, increased expression of PD-L1 is highly correlated with the aggressiveness of the cancer. One particular experiment examined 196 tumor specimens that had been extracted from patients with renal cell carcinoma (kidney tumors). In these tumor samples, high expression of PD-L1 was positively associated with increased tumor aggressiveness and a those patients that had higher expression of PD-L1 have a 4.5-fold increased risk of death (see Thompson RH, et al., Proc Natl Acad Sci USA 101 (49): 17174–9). In patients with cancer of the ovaries, those tumors with higher PD-L1 expression had a significantly poorer prognosis than those with lower PD-L1 expression. The more PD-L1 these tumors expressed, the fewer tumor-hunting T cells (CD8+ T cells) were present (see Hamanishi J, and others, Proc Natl Acad Sci USA 104 (9): 3360–5).

So the Xu paper proposes that we introduce genetically engineered cells, which are already at risk for mutations in the first place, into the body, that constitutively express PD-L1, a protein known to be highly expressed in the most aggressive and lethal tumors. Does this sound like a good idea?

With respect to CTLA4-Ig, this is a cell-bound version of a drug that has been approved as an anti-transplantation rejection drug called Belatacept (Nulojix), made by Bristol-Myers-Squibb. Since this is a cell-bound version of this protein, it will almost certainly not have the systemic effects of Belatacept, and if the cells manage to release a certain amount of soluble CTLA4-Ig, it is likely to be very little and have no biological effect.

Therefore, this strategy, while interesting, does come with its own share of risks and caveats.