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BACKGROUND: Despite recent advances, there is an urgent need for agents targeting HER2-expressing cancers other than breast cancer. We report a phase I study (NCT01730118) of a dendritic cell (DC) vaccine targeting HER2 in patients with metastatic cancer or bladder cancer at high risk of relapse. PATIENTS AND METHODS: Part 1 of the study enrolled patients with HER2-expressing metastatic cancer that had progressed after at least standard treatment and patients who underwent definitive treatment for invasive bladder cancer with no evidence of disease at the time of enrollment. Part 2 enrolled patients with HER2-expressing metastatic cancer who had progressed after anti-HER2 therapy. The DC vaccines were prepared from autologous monocytes and transduced with an adenoviral vector expressing the extracellular and transmembrane domains of HER2 (AdHER2). A total of five doses were planned, and adverse events were recorded in patients who received at least one dose. Objective response was evaluated by unidimensional immune-related response criteria every 8 weeks in patients who received at least two doses. Humoral and cellular immunogenicity were assessed in patients who received more than three doses. RESULTS: A total of 33 patients were enrolled at four dose levels (5 × 106, 10 × 106, 20 × 106, and 40 × 106 DCs). Median follow-up duration was 36 weeks (4-124); 10 patients completed five doses. The main reason for going off-study was disease progression. The main adverse events attributable to the vaccine were injection-site reactions. No cardiac toxicity was noted. Seven of 21 evaluable patients (33.3%) demonstrated clinical benefit (1 complete response, 1 partial response, and 5 stable disease). After ≥3 doses, an antibody response was detected in 3 of 13 patients (23.1%), including patients with complete and partial responses. Lymphocytes from 10 of 11 patients (90.9%) showed induction of anti-HER2 responses measured by the production of at least one of interferon-gamma, granzyme B, or tumor necrosis factor-alpha, and there were multifunctional responses in 8 of 11 patients (72.7%). CONCLUSIONS: The AdHER2 DC vaccine showed evidence of immunogenicity and preliminary clinical benefit in patients with HER2-expressing cancers, along with an excellent safety profile. It shows promise for further clinical applications, especially in combination regimens.

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Centers involved with collecting the starting material for cell and tissue therapies are obligated to protect the recipient's and donor's health and safety. All donors face risks during and after the collection which can be minimized by prescreening donors and excluding those that the collection would place at increased risk of physical harm. Another important part of protecting donors is the use of appropriate collection facilities. Donor risk can also be reduced by using specially designed collection devices and ancillary equipment, using only trained collection staff and limiting the volume or quantity of biologic material collected. Donors should be monitored during and after the collection for adverse events, and should adverse events occur, they should be promptly and appropriately treated. Protecting the safety of cell, gene and tissue donors is particularly difficult because of the wide variety in the types of donors and material collected. Biological material used to manufacture cell and tissue therapies is collected from healthy volunteers, matched-related, matched-unrelated and autologous donors. Precautions should be taken to ensure that the team of medical professionals evaluating related donors is not the same as the team caring for the transplant recipient in order to be sure that the donor evaluation is not biased and the donor is not coerced into donating. In conclusion, protecting cell and tissue donors requires the use of the practices developed to protect blood donors and the implementation of many other measures.

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A repository of cryopreserved bone marrow stromal cell (BMSC) products prepared from marrow aspirates of healthy subjects has been created and is being used to treat patients with inflammatory bowel disease, cardiovascular disease, and acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. New methods of manufacturing BMSCs are being investigated including the use of an automated bioreactor for BMSC expansion and the replacement of fetal bovine serum with human platelet lysate as a media supplement. Efforts are also being made to identify markers that can be used to assess the potency of BMSCs.

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BACKGROUND: Bone marrow stromal cells (BMSCs) are being used to treat a variety of conditions. For many applications a supply of cryopreserved products that can be used for acute therapy is needed. The establishment of a bank of BMSC products from healthy third party donors is described. METHODS: The recruitment of healthy subjects willing to donate marrow for BMSC production and the Good Manufacturing Practices (GMP) used for assessing potential donors, collecting marrow, culturing BMSCs and BMSC cryopreservation are described. RESULTS: Seventeen subjects were enrolled in our marrow collection protocol for BMSC production. Six of the 17 subjects were found to be ineligible during the donor screening process and one became ill and their donation was cancelled. Approximately 12 ml of marrow was aspirated from one posterior iliac crest of 10 donors; one donor donated twice. The BMSCs were initially cultured in T-75 flasks and then expanded for three passages in multilayer cell factories. The final BMSC product was packaged into units of 100 × 106 viable cells, cryopreserved and stored in a vapor phase liquid nitrogen tank under continuous monitoring. BMSC products meeting all lot release criteria were obtained from 8 of the 11 marrow collections. The rate of growth of the primary cultures was similar for all products except those generated from the two oldest donors. One lot did not meet the criteria for final release; its CD34 antigen expression was greater than the cut off set at 5%. The mean number of BMSC units obtained from each donor was 17 and ranged from 3 to 40. CONCLUSIONS: The production of large numbers of BMSCs from bone marrow aspirates of healthy donors is feasible, but is limited by the high number of donors that did not meet eligibility criteria and products that did not meet lot release criteria.

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