Clinical Trials within U.S.: Cancer

STEM CELL RESEARCH is playing an increasingly relevant role both in clinical and experimental oncology at the present time. On the one hand, the identification of cancer stem cells in different neoplasms noticeably modified general comprehension about cancer biology; on the other, the delivery of such growing knowledge from bench to bedside is starting to affect therapeutic choices in cancer treatment.

Bone marrow transplants (BMTs) were the first application of stem cells in cancer therapy. Available since 1956, and subsequently improved, this treatment is now considered a current therapeutic option for many hematological neoplasms, and much interest has been generated about the possibility of extending such procedures to solid tumors. BMT is more commonly performed as a hematopoietic stem cell transplant (HSCT), in which the infusion of HSCs previously harvested through a conditioning therapy (high—dose chemo—radiotherapy) can entirely rebuild the marrow in 10–20 days. Although the traditional HSCT needs a complete myeloablation, which means that the host's marrow is completely destroyed before the infusion of the donor's HSCs, nonmyeloablative or reduced—intensity transplants require less intense conditioning regimens, which are employed just to suppress the patient's immune response so that the donor's HSC can efficiently engraft. A large amount of clinical data prove HSCT to be an effective treatment in leukemia and other hematological malignancies: With more than 200,000 transplants performed worldwide, HSCT is an advisable treatment in patients with acute myeloid leukemia who achieved a first complete remission, in patients with acute lymphoblastic leukemia obtaining a poor response to chemotherapy, and also in patients suffering from chronic lympho—cytic leukemia, some high—risk lymphomas, and myelodysplastic syndromes.

Initially employed for solid tumor therapy as autografts or allografts with rescue purposes, and aiming to overcome myelotoxicity caused by the high—dose antineoplastic treatment, HSCT was demonstrated afterward to be directly responsible for an observed antitumor effect in the allograft setting. Allogeneic HSCT has in fact been proven to be a resourceful sort of immunotherapy both in mye—loablative and in nonmyeloablative transplants: an antitumor immune response mediated by the graft, defined as graft versus leukemia or graft versus tumor (GVT), has been respectively demonstrated in a hematological and a solid cancer context.

The relatively high transplant—related mortality and a more complicated patient management compared with the standard treatments contributed to the scarce diffusion of such therapeutic options in the past, but the recent introduction of nonmyeloablative protocols increased interest in this treatment, as it demonstrated many fewer risks. In the recent past, many clinical trials in and outside [Page 119]the United States tested allogeneic HSCT as immu—notherapy for solid tumors; renal cell carcinoma, breast cancer, ovarian cancer, and testicular germ cell tumors have been the most investigated.

Regarding renal cell carcinoma, in 2000, Childs and colleagues first observed a tumor regression in 10 of 19 patients treated with nonmyeloablative HSCT (53 percent)—a result that was confirmed by a 2002 update, with a 48 percent response rate. In 2005 Artz and colleagues from the University of Chicago published a review including 14 studies and 163 patients, reporting an overall response rate of 24 percent. Many phase 1–2 clinical trials are currently ongoing within the United States; some are testing the feasibility, the safety, and the efficacy of the procedure, and in many others, HSCT is combined with other forms of adoptive immunotherapy such as donor lymphocyte infusion to evaluate whether such additional treatments have an effect on HSCT efficacy.

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