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Are Stem Cells Therapies in the Opposite of the 'Hype Cycle'?


By Anette Breindl
Science Editor

ATLANTA – Michele de Luca, of the University of Modena's Center for Regenerative Medicine, introduced himself in an unusual fashion for a plenary speaker at a hematology convention. "I have nothing to do with blood," he told his audience at Tuesday's Presidential Symposium on stem cells at the American Society of Hematology's (ASH) annual meeting.

Instead, de Luca studies corneal regeneration after epithelial stem cell transplants. In his talk, he fascinated (if that is the term) his audience with Bunuel-like videos of eye surgery; insulted them with the assertion that "very few clinicians keep their brain on"; and mollified them with self-effacing comments on his own scientific prowess: "Most people say there is one important figure in each paper. I have one important figure in four papers."

Aside from his showmanship, though, one striking thing about his talk was how routine the surgery he described is.

De Luca's clinical collaborators have operated on about 1,500 patients, and have had success in restoring vision in roughly 75 percent of them. His current goal is to bring that number up to nearly 100 percent.

Another staple of ASH is studies on hematopoietic stem cell or bone marrow transplants – how to prepare patients for them, who they work for and in which indications.

It seems odd that an approach that is so routine in some clinical settings should at the same time be saddled with a cottage industry of charlatans. In another general session at the ASH meeting, Douglas Sipp, of the RIKEN Institute for Developmental Biology, told the audience about "Stem Cell Tourism" – Internet offers for stem cell therapy that would be funny if the desperation fueling their successes were not so heartbreaking.

"Stem cells," Sipp told the audience, "have become something of a marketing concept." And as a result, on the Internet they are being offered as combination treatments with agents that are decidedly different from the targeted drugs and chemotherapies at ASH.

Here, stem cells are offered in combination with everything from nutraceuticals (flavors include Edelweiss) to astrology, for every conceivable indication, including "disease not specified," which Sipp translated as, "We don't actually know what you have, but we know someone who will take your money."

Why stem cells of all therapies should simultaneously be routinely used in some indications and attract what seems like more than their share of snake oil salesmen is something of a mystery. Perhaps it is due to the potential breadth of their applications, historical uncertainties about their regulation or the fact that they make it seem possible, in some fundamental sense, to outwit time.

But whatever the reason, Alan Trounson, president of the California Institute for Regenerative Medicine (CIRM), told the audience that stem cell charlatans harm more than just the people they get their hands on.

"There's a tragedy out there for patients, but there's also a tragedy out there for the whole field," he said. The more patients are harmed by unscrupulous frauds, "the harder it will be to get them to accept lifesaving treatments down the line."

Trounson said he believes that the way to combat stem cell charlatanerie is through two parallel approaches.

In the short term, it is necessary to educate consumers about stem cells in a way that remains realistic while it is accessible to the average potential patient.

The websites advertising miracle healing through stem cells, Trounson pointed out, can be "seductive and compelling. The alternative for finding that information doesn't seem to exist."

He called websites that are dedicated to providing legitimate clinical trials information "stale and difficult to navigate" as well as highly technical.

Over time, however, the way to shut down stem cell charlatans is by drying up their market – through providing a legitimate alternative for patients seeking experimental cell-based treatment. "There's a need for a network of genuine stem cell clinics," he said. And such clinics, he added, should include stem cell counselors that, like genetic counselors do, can provide a realistic picture of the potential risks and benefits to patients. The CIRM hopes to help build, via its funding abilities, such a network.

In other ASH news:

• Acetylon Pharmaceuticals Inc., of Boston, reported preliminary results from a Phase I/II study showing that HDAC6 inhibitor ACY-1215 in combination with Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and dexamethasone may provide a well-tolerated treatment option for relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data indicated that ACY-1215 could play a beneficial role of HDAC6 inhibition in MM-related bone disease. In a separate presentation, the company reported preclinical data showing that its selective HDAC1/2 inhibitor could represent a targeted approach for the treatment of sickle cell disease and beta-thalassemia through the induction of disease-corrective fetal hemoglobin in human red blood cell progenitors.

• Aeterna Zentaris Inc., of Quebec City, reported that final Phase II data demonstrated that the combination of perifosine, its oral AKT inhibitor, and Nexavar (sorafenib, Onyx Pharmaceuticals Inc. and Bayer AG) was well tolerated by heavily pretreated patients with relapsed/refractory lymphomas. Furthermore, promising clinical response activity was observed in patients with classical Hodgkin lymphoma, suggesting that this subgroup could represent the target population for future studies. The study involved 40 patients with relapsed/refractory lymphomas who had failed second or subsequent-line salvage chemotherapy. There were three patients with diffuse large B-cell lymphoma, three with follicular lymphoma, one with Waldenstrom macroglobulinemia, eight with chronic lymphocytic leukemia (CLL) and 25 with classical Hodgkin lymphoma. Based on tumor response to the initial four-week perifosine therapy, 36 of 40 patients who achieved less than a partial response (PR) were subsequently administered the perifosine/sorafenib combination therapy. Median duration of combination therapy was four months. Four CLL patients, who achieved at least a PR with perifosine alone, went off study and continued with single-agent therapy with a median duration of response of 10 months. For the 36 patients treated with combination therapy, eight (22 percent) had PRs, 15 (42 percent) had stable disease and 13 (36 percent) had progressive disease.

• Ariad Pharmaceuticals Inc., of Cambridge, Mass., reported 12-month follow-up data from its PACE trial of ponatinib in chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) showing that 57 percent of CML patients achieved major hematologic response. That included 50 percent of patients with the T315I mutation. There were 444 patients in six pre-specified cohorts receiving 45 mg of ponatinib daily enrolled in the trial, including 177 with advanced disease. In a separate presentation, Ariad reported updated molecular responses from its Phase I and pivotal Phase II (PACE) trials of ponatinib for CML or Ph+ ALL showing that 51 percent of chronic phase CML patients achieved a major molecular response (MMR) in the Phase I trial at a median follow-up time of 30 months, and 34 percent achieved MMR in the PACE trial at a median time of 15 months. The Phase I trial enrolled 81 patients with hematologic cancers, including 43 with chronic-phase CML. The PACE trial enrolled 449 patients with CML or Ph+ ALL.

• Array BioPharma Inc., of Boulder, Colo., reported Phase II data showing that patients with triple-refractory multiple myeloma and a median number of 10 prior treatment regimens demonstrated a 22 percent overall response rate when given ARRY-520, a kinesin spindle protein inhibitor, plus low-dose dexamethasone. Researchers also presented data showing acute phase protein alpha-1-acidic glycoprotein (AAG) may be a biomarker enabling better patient selection for response to ARRY-520. Patients with lower AAG levels showed an overall response rate of 33 percent, with a median time of study of 6.2 months. The company also reported interim data from a trial testing ARY-520 in combination with Kyprolis (carfilzomib, Onyx Pharmaceuticals Inc.) in patients with relapsed or refractory MM who are refractory or intolerant to Velcade (bortezomib, Millennium: The Takeda Oncology Co.). Results showed early signals of activity, with a 56 percent clinical benefit rate and manageable side-effect profile.

• Celator Pharmaceuticals Inc., of Princeton, N.J., reported new data from a Phase IIb study showing that CPX-351 for acute myeloid leukemia (AML) was highly active in all patient subgroups and had the greatest response rate in patients with secondary AML and adverse cytogenetics. The study compared CPX-351 to cytarabine and daunorubicin in patients between the ages of 60 and 75 with previously untreated AML, with a primary endpoint of complete response plus complete response with incomplete recovery of neutrophils or platelets.

• Celgene International Sarl, of Boudry, Switzerland, a unit of Celgene Corp., said a Phase II study of Revlimid (lenalidomide) plus Vidaza (azacitidine) in patients 60 or older with untreated acute myeloid leukemia showed an overall response rate of 41 percent, with 28 percent achieving a complete response. The study enrolled 42 patients who received azacitidine for seven days, followed by lenalidomide on days eight through 28 of a 42-day cycle, for 12 cycles. Median overall survival was 20 weeks for all patients, and 69 weeks for those who responded to the therapy. In a separate presentation, Celgene reported data from a Phase III open-label study (MM-003) of pomalidomide with low-dose dexamethasone compared with high-dose dexamethasone in refractory multiple myeloma patients who had been treated with Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and lenalidomide. The trial met its primary endpoint of improving progression-free survival (PFS) (3.6 months vs. 1.8 months). The company also reported data from its EMERGE Phase II study of Revlimid (lenalidomide) in patients with previously treated mantle cell lymphoma, which produced an overall response rate of 28 percent and a complete response rate of 8 percent, with a median duration of response of 16.6 months. Median PFS was four months.

• Glycomimetics Inc., of Gaithersburg, Md., presented data from a pilot study of GMI-1070 showing that the drug affected biomarkers significant to sickle cell disease. The drug had a significant effect on biomarkers associated with cell adhesion, activation and coagulation. The company also presented two posters featuring preclinical progress of GMI-1271 in acute myeloid leukemia.

• ImmunoGen Inc., of Waltham, Mass., presented Phase I data showing that IMGN901 in combination with Revlimid (lenalidomide, Celgene Corp.) and dexamethasone in CD56-expressing relapsed or relapsed/refractory multiple myeloma produced a 64 percent clinical response in patients, defined as a minimal response or better, and 31 percent of patients had stable disease. The trial testing IMGN901, a drug consisting of the company's DM1 cancer cell-killing agent attached to CD56-binding antibody lorvotuzumab, enrolled a total of 44 patients, most of whom had previously received Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and/or Revlimid. Median time to progression in the study was 7.7 months for the regimen containing IMGN901 at 75 mg/m2.

• Immunomedics Inc., of Morris Plains, N.J., reported that the subcutaneous administration of veltuzumab as a single agent demonstrated promising activity in patients with relapsed immune thrombocytopenia, even in more heavily treated patients with chronic disease and in patients with chronic lymphocytic leukemia. For 42 evaluable patients, the overall objective response rate was 50 percent, with 12 patients (29 percent) having a complete response, meaning their platelet levels rose to or above 100,000 per uL. Veltuzumab is a second-generation humanized anti-CD20 antibody. In a separate presentation, the company reported that small, repeated doses of epratuzumab labeled with radioisotope yttrium-90 (90Y) demonstrated therapeutic activity in two clinical trials in patients with aggressive non-Hodgkin's lymphoma (NHL). In a Phase II trial, a total of 75 patients between the ages of 60 and 80 were enrolled to receive six cycles of R-CHOP therapy, with 61 patients eligible for two consolidation treatments of 90Y-epratuzumab at 15 mCi/m2. The overall response rate after six cycles of R-CHOP therapy was 94.6 percent (71/75), with 52 patients (69.3 percent) achieving a complete or unconfirmed complete response and 19 patients (25.3 percent) reporting a partial response.

• Incyte Corp., of Wilmington, Del., reported analyses from several studies of JAK inhibitor Jakafi (ruxolitinib), including long-term results from both COMFORT-1 and COMFORT-2 trials showing that patients with myelofibrosis (MF) had improved survival when treated with Jakafi over placebo and best available therapy, suggesting an overall survival benefit in patients with intermediate or high-risk MF. Data from the two-year follow-up also showed that improvements in quality-of-life measures and reductions in spleen volume were maintained with continued treatment. Other data presented included results from a three-year follow-up of patients with polycythemia vera (PV) in a Phase II trial, showing that ruxolitinib treatment resulted in durable response rates by modified European Leukemia Net criteria and improvement in PV-related symptoms.

• Jazz Pharmaceuticals plc, of Dublin, Ireland, reported data from a large safety trial in patients who had developed a hypersensitivity to E. coli-derived asparaginase who were treated with Erwinaze (asparaginase Erwinia chrysanthemi) as part of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia. Data summarizing results in 940 patients described an adverse event profile consistent to the known safety profile of Erwinaze.

• Millennium: The Takeda Oncology Co., of Cambridge, Mass., presented data from a Phase I study investigating once-a-week proteasome inhibitor MLN9708 in patients with relapsed or refractory systemic light-chain amyloidosis (AL). The primary objectives were to determine the safety, tolerability and maximum-tolerated dose (MTD) and to determine the dose for future development. Once the MTD was reached, two expansion cohorts were enrolled, one with proteasome inhibitor-naïve patients (n = 5) and one with proteasome inhibitor-exposed patients (n = 12). The MTD and dose for future development was established as 4 mg. In a separate presentation, Millennium reported results from a Phase I trial of Adcetris (brentuximab vedotin) in combination with chemotherapy for the treatment of patients with newly diagnosed advanced stage Hodgkin lymphoma. Cohorts of patients received escalating doses of Adcetris ranging from 0.6 mg/kg to 1.2 mg/kg every two weeks concomitantly with ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) or a dose of 1 .2 mg/kg every two weeks concomitantly with AVD, which removes bleomycin from the regimen. Results from the Adcetris plus AVD arm showed 24 of 25 patients (96 percent) had a complete remission (CR), while 21 of 22 (95 percent) of patients treated with Adcetris plus ABVD had a CR.

• Novartis AG, of Basel, Switzerland, reported long-term Phase III data showing that Philadelphia chromosome-positive chronic myelogenous leukemia patients receiving Tasigna (nilotinib) achieved significantly deeper molecular responses vs. Glivec (imatinib). Those results were seen in both newly diagnosed patients and those switching to Tasigna after long-term treatment with Glivec.

• Onconova Therapeutics Inc., of Newtown, Pa., reported data from a Phase I/II study showing that single-agent rigosertib was well tolerated and achieved effects that were in line with previous studies in myelodysplastic syndromes and acute myeloid leukemia. Data from a Phase I study testing the multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies, also found the drug to be well tolerated as a single agent, with no dose-limiting toxicities.

• Pharmacyclics Inc., of Sunnyvale, Calif., reported follow-up findings from an ongoing open-label Phase II study suggesting that in patients with relapsed or refractory mantle cell lymphoma, both Velcade (bortezomib, Millennium: The Takeda Oncology Co.)-naïve and Velcade-exposed, oral agent ibrutinib (PCI-32765) resulted in high and durable responses and was generally well tolerated. The study enrolled 111 patients to receive ibrutinib, a Bruton's tyrosine kinase inhibitor, and the median follow-up time was 9.2 months, with a range of time to response to treatment of 1.4 months to 16.4 months. Results showed an overall response rate of 68 percent and a median progression-free survival estimated at 13.9 months. Shares of Pharmacyclics (NASDAQ:PCYC) gained $4.45, or 7.6 percent, to close Tuesday at $63.25.

• Sangamo BioSciences Inc., of Richmond, Calif., presented preclinical data demonstrating successful application of its In Vivo Protein Replacement Platform. Based on the firm's zinc finger DNA-binding protein genome-editing technology, the platform is designed to enable the permanent production of therapeutic proteins from the liver with a single systemic treatment, potentially providing curative treatments for a range of monogenic diseases, including hemophilia and lysosomal storage diseases such as Gaucher's and Fabry diseases. Among data presented were results showing that a single systemic treatment enabled stable liver-specific production of human Factor IX protein, the clotting factor abset in hemophilia B, reaching or exceeding 100 percent of normal circulating levels.

• Seattle Genetics Inc., of Bothell, Wash., reported results from two ongoing Phase II trials of Adcetris (brentuximab vedotin) in patients with relapsed cutaneous T-cell lymphoma (CTCL). One trial is enrolling patients with mycosis fungoides (MF) or Sezary syndrome. Twenty patients have been enrolled to date with a median of six prior systemic therapies. The primary endpoint of the trial is clinical response rate. Secondary endpoints include correlation of clinical response with CD30 expression levels, duration of response and safety. Fourteen of 20 patients (70 percent) achieved an objective response across all stages of disease. At the time of analysis, 14 patients had a partial response, one patient had stable disease and four patients had progressive disease. Data also were presented from a Phase II trial evaluating the use of Adcetris in CD30-positive CTCL patients. Thirty-one of 46 patients (67 percent) achieved an objective response. In separate presentations, Seattle Genetics highlighted clinical data from two antibody-drug conjugate (ADC) programs in development by partner South San Francisco-based Genentech Inc., a member of the Roche Group. Phase I data from both ADCs, an anti-CD22 ADC (DCDT2980S, RG7593) and an anti-CD79b ADC (DCDS4501A, RG7596), demonstrated antitumor activity in relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) patients at generally well-tolerated doses. A Phase I trial is being conducted to evaluate DCDS4501A in patients with relapsed or refractory B-cell NHL. Among all 32 patients evaluable for efficacy, 10 patients (31 percent) had objective responses to single-agent DCDS4501A. Among the 17 patients treated at doses greater than or equal to 1 .8 mg/kg, eight patients (47 percent) had objective responses. A Phase I trial is being conducted to evaluate DCDT2980S in patients with relapsed or refractory B-cell NHL. Among all 33 patients evaluable for efficacy, nine (27 percent) had objective responses to single-agent DCDT2980S. Among the 17 patients treated at doses greater than or equal to 1.8 mg/kg, seven patients (41 percent) had objective responses, including one complete response and six partial responses.

Researchers from a consortium including the University of Michigan, Washington University in St. Louis, Mie (Japan) University Hospital and others reported findings from a study targeting histone deacetylase (HDAC) inhibitors as a strategy to prevent graft-vs.-host disease (GVHD). They tested the hypothesis that HDAC inhibition will be safe and reduce the severity of GVHD in patients undergoing matched related donor (MRD) reduced intensity conditioning (RIC) allogeneic HSCT by enrolling 45 patients at two centers in a Phase I/II trial that combined the HDACi, Zolinza (vorinostat, Merck & Co. Inc.), with a standard GVHD prophylaxis regimen consisting of tacrolimus and mycophenolate mofetil (MMF) and comparing them with historical controls. The primary endpoint was the cumulative incidence of Grade 2-4 acute GVHD (aGVHD). Results showed no cases of graft failure or excessive toxicity or death attributable to vorinostat. The incidence of aGVHD was globally diminished in all target organs, and all but one patient responded rapidly to standard steroid therapy. The incidence of relapse also was similar between the study and controls.

A consortium of researchers from the Blood and Marrow Transplant Clinical Trials Network showed there was no survival advantage after double umbilical cord blood (UCB) compared to single UCB transplant in children with hematological malignancy. The Phase III trial compared one-year overall survival in the two study arms using an intent-to-treat analysis. Secondary objectives included comparisons of engraftment, acute and chronic graft-vs.-host disease (GVHD), NRM, relapse and disease-free survival. Results showed a median follow-up of surviving patients of 25 months across both study arms, with 92 percent of patients in remission and 60 percent of those in second or subsequent remission. While recipients of two units had a higher incidence of acute GVHD, relapse risk was unchanged.