Cancer Immunotherapy with Alloreactive Lymphocytes
Editorial
The New England Journal of Medicine -- September 14, 2000 -- Vol. 343, No. 11
In this issue of the Journal, Childs and colleagues present preliminary evidence that in patients with
metastatic renal-cell cancer, infusions of allogeneic hematopoietic stem cells after a preparative regimen
that does not ablate the bone marrow (nonmyeloablative stem-cell transplantation) may be an effective
treatment. (1) This report opens new therapeutic possibilities not only for metastatic renal-cell cancer but also for other solid tumors that are resistant to conventional chemotherapy and radiotherapy.
The basis of this treatment rests in part on observations that were made in patients who were treated with the classic approach to certain types of leukemia: very high doses of chemotherapy in order to destroy both malignant and normal cells in the bone marrow (myeloablative therapy) and then an allogeneic bone marrow transplant from a healthy donor in order to restore the hematopoietic system. Fourteen years ago, it was discovered that a relapse of leukemia after such treatment could in some cases be controlled by further infusions of lymphocytes from the same marrow donor. (2) The donor lymphocytes most likely destroyed the resurgent leukemia cells by an immune mechanism called the graft-versus-leukemia effect. A parallel phenomenon is the graft-versus-solid-tumor effect after allogeneic bone marrow transplantation in mice (3,4) and humans. (5,6) Presumably, T cells of the helper (CD4) and cytotoxic (CD8) types in the allograft participate in these phenomena, but the relevant antigens (tumor-specific antigens, the recipient's histocompatibility antigens, or both) have not been identified. Nevertheless, this mechanism is plausible enough for us to regard allogeneic bone marrow transplantation or donor-lymphocyte infusion as a form of anticancer immunotherapy.
Such an approach, however, seemed unworkable in patients with cancer who were treated with standard bone marrow transplantation protocols, owing to the severe toxicity and high mortality rates associated with the approach. (6) Another important drawback is that donor lymphocytes can attack not only malignant cells but also the normal cells and tissues of the recipient, thereby causing a condition called graft-versus-host disease. This complication can be serious and is sometimes fatal. (6) However, although it is common, graft-versus-host disease is not an inevitable complication of donor-lymphocyte infusion and may not be essential for its therapeutic effect. (2)
To succeed, immunotherapy with allogeneic lymphocytes requires two elements: long-term engraftment of the donor lymphocytes, which means that a way must be devised to prevent the recipient from rejecting the donor's T cells, and avoidance of the toxicity and mortality related to the procedure. Studies in laboratory animals have shown that sustained engraftment of donor hematopoietic stem cells can be accomplished with the use of well-tolerated conditioning regimens that cause immunosuppression without ablating the bone marrow. (3,7,8) Similar observations were recently reported in clinical studies, and these findings have led to the use of nonmyeloablative stem-cell transplantation for other indications, including solid tumors. (9,10) When this approach is used for the treatment of cancer, the goal is not to kill every tumor cell but to enable the recipient to accept the foreign lymphocytes. These donor lymphocytes, in principle, have the capacity to attack the tumor in the same way they would destroy a foreign graft. In retrospect, the standard therapeutic strategy in bone marrow transplantation overestimated the anticancer potential of even very high doses of chemotherapy and radiotherapy and underestimated the efficacy of immunotherapy mediated by allogeneic donor lymphocytes.
Nonmyeloablative hematopoietic stem-cell transplantation has been used to treat acute and chronic leukemia, lymphoma, multiple myeloma, and certain genetic diseases, such as enzyme-deficiency disorders, Fanconi's anemia, and thalassemia major. (10) With growing clinical experience, it became evident that this approach could also be used for the immunotherapy of metastatic solid tumors. This potential was reinforced by demonstrations of the graft-versus-tumor effects of allogeneic lymphocytes in animals pretreated with nonmyeloablative conditioning. (3,4,11) For this reason, the success of the nonmyeloablative protocol used by Childs et al. in treating metastatic renal-cell cancer is cause for hope. The therapy they used has two main phases: pretreatment with immunosuppressive agents to induce acceptance by the recipient of HLA-matched hematopoietic stem cells from a normal sibling, followed by one or more infusions of donor lymphocytes to attack the tumor. Additional immunosuppressive therapy with cyclosporine to prevent or ameliorate graft-versus-host disease was also required in most patients. Ten of 19 patients (53 percent) who enrolled in the study had a measurable response, and 3 patients had complete, sustained responses.
Although these results are promising and should encourage similar treatment strategies for use against other metastatic tumors, the procedure used by Childs et al. is not entirely satisfactory. Despite regression of the tumor in some patients, there was severe graft-versus-host disease, progression, or both in others. Two patients died after receiving this treatment. Clearly, the procedure needs further refinement to minimize complications and improve its efficacy.
The concordance between a graft-versus-tumor effect and the occurrence of graft-versus-host disease in most of the patients studied by Childs et al. suggests that the antitumor effect of donor lymphocytes is mediated at least in part by an immune reaction against tumor cells that display the recipient's histocompatibility antigens. Nevertheless, preclinical (3,11) and early clinical (9,10,12) studies indicate that both graft-versus-leukemia effects and graft-versus-tumor effects can occur in the absence of graft-versus-host disease. Indeed, in two patients studied by Childs et al., a graft-versus-tumor effect was observed in the absence of graft-versus-host disease at the time of disease regression. They also found that regression of metastases was often delayed for months after the onset of graft-versus-host disease, suggesting that the antitumor effector cells may be distinct from the T cells that cause graft-versus-host disease.
Several approaches may increase the efficacy and reduce the risks of immunotherapy with donor lymphocytes. Recent experiments in my laboratory suggest that one can improve the anticancer effects while eliminating or reducing the severity of graft-versus-host disease by using immune rather than naive donor T cells. Such immune T cells can be generated in vitro by culture of lymphocytes with tumor-specific peptides of the patient's tumor cells. Donor cytotoxic and helper T cells can be generated in vitro by a method that prevents the reactivity of the T cells to the prospective host's histocompatibility antigens, leaving a population of tumor-specific T cells. Another approach, which could be used in patients without a histocompatible sibling, involves T-cell-depleted hematopoietic stem cells, which the recipient will not reject, followed by the administration of progressively larger numbers of donor T cells (or tumor-specific T cells), with careful titration, until all detectable tumor cells have been eliminated or there is evidence of graft-versus-host disease. It is also possible to manipulate the donor lymphocytes in vitro by inserting a suicide gene, such as the herpes simplex virus thymidine kinase gene. This provides the physician with the possibility of destroying the infused lymphocytes in patients with uncontrolled graft-versus-host disease. (13)
Although much work remains, the proof of two principles is already at hand: allogeneic T cells can eradicate renal-cancer cells, and donor lymphocytes can survive in the host after nonmyeloablative conditioning. Future progress will depend on the achievement of safer and better controlled antitumor immunotherapy that is independent of graft-versus-host responses, and this remains a challenge for further research.
Shimon Slavin, M.D.
Hadassah University Hospital
Jerusalem 91120, Israel
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Abstract of referenced article...
Regression of Metastatic Renal-Cell Carcinoma after
Nonmyeloablative Allogeneic Peripheral-Blood Stem-Cell Transplantation
Richard Childs, Allen Chernoff, Nathalie Contentin, Erkut Bahceci, David Schrump, Susan Leitman, Elizabeth J. Read, John Tisdale, Cynthia Dunbar, W. Marston Linehan, Neal S. Young, A. John Barrett, Emmanuel Clave, Diane Epperson, Virginia Mayo
Abstract
Background. Since allogeneic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematologic cancers, we sought to induce analogous graft-versus-tumor effects in patients with metastatic renal-cell carcinoma by means of nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.
Methods. Nineteen consecutive patients with refractory metastatic renal-cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of a peripheral-blood stem-cell allograft from an HLA-identical sibling or a sibling with a mismatch of a single HLA antigen. Cyclosporine, used to prevent graft-versus-host disease, was withdrawn early in patients with mixed T-cell chimerism or disease progression. Patients with no response received up to three infusions of donor lymphocytes.
Results. At the time of the last follow-up, 9 of the 19 patients were alive 287 to 831 days after transplantation (median follow-up, 402 days). Two had died of transplantation-related causes, and eight from progressive disease. In 10 patients (53 percent) metastatic disease regressed; 3 had a complete response, and 7 had a partial response. The patients who had a complete response remained in remission 27, 25, and 16 months after transplantation. Regression of metastases was delayed, occurring a median of 129 days after transplantation, and often followed the withdrawal of cyclosporine and the establishment of complete donor-T-cell chimerism. These results are consistent with a graft-versus-tumor effect.
Conclusions. Nonmyeloablative allogeneic stem-cell transplantation can induce sustained regression of metastatic renal-cell carcinoma in patients who have had no response to conventional immunotherapy. (N Engl J Med 2000;343:750-8.)
Source Information
From the Hematology Branch, National Heart, Lung, and Blood Institute (R.C., N.C., E.B., C.D., N.S.Y., A.J.B.); the Urologic Oncology Branch (A.C., W.M.L.) and the Surgery Branch (D.S.), Division of Clinical Sciences, National Cancer Institute; the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center (S.L., E.J.R.), and the Molecular and Clinical Hematology Branch (J.T.), National Institute of Diabetes and Digestive and Kidney Diseases -- all at the National Institutes of Health, Bethesda, Md. Address reprint requests to Dr. Childs at the Hematology Branch, NHLBI/NIH, 10/7C103, 10 Center Dr., M.S.C. 1652, Bethesda, MD 20892-1652, or at childsr@nih.gov.
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