At the end of the year I analyze results of clinical studies in cell therapy. Today, I’d like to highlight 10 most significant, in my opinion, clinical studies with published results. Taking in account excellent safety profile of most cellular therapies, I was trying to focus on efficacy and long-term outcomes. Do cells really work? That’s what we are care about. Please discuss your favorite (published) clinical studies from 2014 in comments!
1. First results of embryonic stem cell-based trial
Since first isolation of human embryonic stem cells (ESC) in 1998 and approval of the first clinical trial by FDA in 2010 (Geron corp.), we have been waiting any safety results after transplantation of this type of cells into human. Finally, this year, preliminary results of Phase 1/2 clinical trials, conducted by Ocata Therapeutics in US, were published. The authors concluded that transplantation of ESC-derived product into the eye is safe in mid-term (up to 3 years). I think, this is single most significant clinical study in the whole history of embryonic stem cell field.
2. Safety and efficacy of CAR T-cells in pediatric ALL
Immunocellular therapies by gene-modified T-cells in oncology, continues to impress us by good results. One of the most notable highlights of 2014 was a study by Upenn/ CHOP group, published in NEJM. Infusions of so-called CAR-19 T-cells allowed to achieve 90% complete remission in “no option” children with ALL. These results were confirmed in the other independent CART-19 study, conducted at NCI.
3. Historic phase 3 trial in systemic sclerosis
There are very few cell therapy trials, which completed Phase 3. This year, results of one such trials were published in JAMA. Hematopoietic stem cell (HSC) transplantation was compared with cyclophosphomide in patients with severe autoimmune disease – diffuse cutaneous systemic sclerosis. 156 patients were enrolled in 10 countries. HSC transplantation conferred beneficial event-free survival, but only at longer follow-up (>4 years). At 1 year time point, survival of patients in HSC group was worse, due to toxicity. Basically, if patients survived the first year after procedure, they lived longer. Toxicity of conditioning regimen is a big concern for any autologous HSC transplantation in autoimmune diseases. Based on results of this trial, each center should decide for itself, if this treatment can be offered as standard of care. We are still awaiting results of analogous big trial, which currently is ongoing in US.
4. CCR5-modified T-cells in HIV
Modification of CCR5 of T- or hematopoietic progenitor cells is a therapeutic approach in HIV, pursued by few research groups. This year, results of the first such study were released. CCR5 was modified by genome editing technique (ZNF) in ex vivo expanded autologous T-cells. The trial was designed to assess safety and feasibility – it passed! As for potential efficacy, HIV RNA was undetectable in 1 and DNA load declined in most of 12 analyzed patients.
5. New generation retroviral vector for cell gene therapy of SCID
Inherited severe combined immunodeficiency (SCID) is a disease, which is treatable with hematopoietic stem cell transplantation or gene therapy. However previous gene therapy trials unveiled serious adverse events – viral vector-induced leukemias in significant number of SCID and WAS patients. New study evaluates results of using new generation vector – self-inactivating γ-retrovirus. This is 1-3 years retrospective outcome analysis of 3 clinical trials. Out of 9 patients 7 recovered T-cell function. No reports on leukemogenesis as complication. So far so good… but 5-10 years outcome should be tracked for long-term safety.
6. First-in-human tissue engineered vaginas
Results of very interesting cohort study, which assessed feasibility of autologous tissue engineered vaginas in patients with aplasia of this organ, were published in Lancet. It was long-term study, conducted by Wake Forest Institute for Regenerative Medicine in Mexico. The study describes only 4 patients, but all with good outcomes – up to 8 years post surgery. This is very unique and important study. It is a showcase for feasibility of organ bioengineering with autologous cells ex vivo. Similar first-in-human study was done this year with tissue engineered noses.
7. Three-years follow-up of HALT-MS trial
Results of government-sponsored Phase 2 trial, assessing autologous HSC transplantation in relapse remitting multiple sclerosis, were recently published. Three years outcome looks good – event-free survival is 78% and progression-free survival is 91%. However, I don’t think we should be over-excited about these results. The trial was not randomized and not controlled. Also, relapse remitting form could be responsive to other treatments. The real problem is secondary progressive MS, where no treatments available. And as for systemic sclerosis case (see above), toxicity of conditioning regimen is still here.
8. Long-term survival and function of fetal neurons in Parkinson’s disease
Very interesting study, assessed long-term survival of fetal neural tissue with dopamine neurons in the brain of 5 patients with Parkinson’s disease. For the first time, detailed morphological examination unveiled survival and function of grafted neurons for as long as 15-18 years after transplantation. Long-term survival correlates with clinical improvement.
9. Expanded cord blood NiCord trial
Results of the trial, sponsored by Israeli company Gamida Cell and conducted at Duke University, significant for 2 folds at least. First, for the first time long-term multilineage engraftment from expanded unit was demonstrated. Second, this is a ticket to use “expaded unit only” without support of “unmanipulated unit” in following trials.
10. Cardiac cell therapy TAC-HFT trial
This is rare example of the study, where 2 different cell types were compared in cardiac disease. Unfortunately, they were directly compared only with placebos, but not with each other. The study is very important and its results were highly anticipated. However, the results of secondary end points (efficacy) assessment are inconclusive. Only 2 out of multiple (>10) secondary end points (12-month viable tissue mass and absolute mass of myocardial scar) appeared significant in MSC vs. placebo. Mononuclear cells were useless. The most important things I learned from this trial – (1) MSC are not impressive (really worth a game?) and (2) better study design needed.
Disclaimer: I’m involved in CAR T-cell therapy clinical trials, conducted at University of Pennsylvania