More than 3,000 stem cell scientists from around the world attended the recent ISSCR meeting.Many promising clinical trials were highlighted at the annual meeting of the International Society of Stem Cell Research (ISSCR).

"Last year was a great year," said Janet Rossant, outgoing president of the ISSCR. "Amazing success stories are coming out in the literature and starting to come toward the clinic."

 Stem Cells and Gene Therapy

One set of trials highlighted were monogenic gene therapy trials. In these trials, blood stem cells are removed from patients with monogenic disorders caused by a single gene mutation. Healthy versions of the genes are slipped into those stem cells via lentiviral vectors. After minimal chemo is administered to create immune system “space,” the corrected stem cells are returned and allowed to grow.

Blood stem cells form all immune cells. The idea is to replace patients’ genetically deficient immune systems with healthy ones.

Luigi NaldiniThe approach remains successful, reported Luigi Naldini of the San-Raffaele Telethon Institute for Gene Therapy in Italy. His institute is running clinical trials, now in their fourth year, offering gene therapy to patients with Wiskott-Aldrich syndrome (WAS) and Metachromatic Leukodystrophy (MLD).

Introducing Naldini, Stanford University stem cell pioneer Irv Weissman said Raffaele, “is recognized as one of world’s leaders, if not the world’s leader, in developing lentiviruses for gene therapy, and bringing them to human therapies, by transfecting populations of cells containing stem cells.”

In WAS, an immunodeficiency, patients are plagued with immune deficiency, bloody diarrhea, and a low platelet count, which can lead to out-of-control bleeding. Most patients develop at least one autoimmune disorder. One-third develop malignancies.

In MLD, a lysosomal storage disease, protective fibers around nerves degenerate. MLD is caused by a deficiency of the arylsulfatse A enzyme. Nerves cease to function properly. Patients die young.

Naldini’s crew reported in two Science papers last summer three patients with WAS showed significant improvement 20-30 months after treatment, as did three patients with MLD. There was robust engraftment of the cells, and robust incorporation of the genes into stem cells and their progeny. Patients blossomed.

Many newer patients are also doing well, leading normal lives, Naldini reported. In MLD patients, he added, corrected cells are crossing the blood-brain barrier, affecting positive brain changes.

“A tour de force,” Weissman said.

 Stem Cells and Cancer Immunotherapy

Another well-received set of trials were described by Michel Sadelain, a Memorial Sloan Kettering oncologist. One reason cancer is so pernicious: tumor cells are “self” cells, so immune systems cannot “see” them, to kill them, as they do viruses.

But as some cancers do prompt immune responses, there is promise there. So cancer immunotherapists have tried for years to help immune systems recognize more cancers by, for example, exposing patients’ tumors to expanded armies of their own T cells in a dish—accompanied by substances that arouse T cells. T cells jangled into such a state of alarm can suddenly recognize cancer cells as harmful, having “seen” them in an alarming environment—and attack those cancer cells after re-infusion into patients.

Still, responses aren’t long-lasting. Sadelain shook up the field last year with his genetically engineered creation of T cells crossed with antibodies—two immune cells in one. He engineered into his hybrid super-immune cells the recognition of certain tumor molecules (antigen). In patients with B cell acute lymphoblastic leukemia, he has seen such impressive results that in 2013 Science made cancer immunotherapy “breakthrough of the year.”

88% Remission Rate Holding Up

At the ISSCR meeting, Sadelain reported more success. Results with his “chimeric antigen receptor” T cells are “holding up,” he said. In February “we reported on the first 16 patients in this trial, this cohort very much enriched in patients with poor prognosis.” He achieved, as that paper notes, an astonishing 88 percent complete remission rate. “The number I want to highlight now is the still 88% rate of complete remission in these patients,” he said. “Exciting.”

Sadelain added he is trying, in vitro, similar approaches with stem cells, more permanent cells of the body, to give patients longer-lived cancer protection, and generate large supplies of T cells. He has created stem cells out of T cells using the induced pluripotent stem cell (iPSC) approach. (He uses genetic engineering to crank back the clock on limited mature cells that don’t proliferate well, turning them into proliferative stem cells. He then expands those stem cells, and cranks the clock forward again, turning them back into T cells.)

The approach has not produced T cells precisely matching natural T cells, but “the answer is yes” when it comes to function: they go after tumors.

“Excellent talk,” said Weissman.

Also discussed were trials for Parkinson’s disease, Multiple Sclerosis, and potential future trials involving cochlear stem cells.