Immunotherapy For Hematologic Malignancies Research Articles

Minor histocompatibility antigens – big in tumour therapy

Technical advances combined with the deciphering of the human genome have facilitated the identification of the molecular nature of human minor histocompatibility (H) antigens. To date, it is believed that minor H antigens result from just any polymorphic protein, regardless of their functional properties. A closer look at the first series of autosomally encoded human minor H proteins reveals a striking functional relationship. Here, we propose that T cells generated after HLA-identical stem cell transplantation (SCT) for malignancies are likely to be directed towards peptides derived from minor H proteins involved in tumourigenesis. This novel insight has important consequences in the search for, and the use of, minor H antigens as immunotherapeutics in stem-cell-based immunotherapy of haematological malignancies and solid tumours.

New approaches in the immunotherapy of haematological malignancies.

Advances in the management of haematological malignancies have allowed to obtain improved remission rates. Nonetheless, relapses impair these results and justify the search for novel therapeutic strategies. Clinical data demonstrate that the immune system plays an important role in the control of haematological malignancies. An increased frequency of haematological malignancies is observed in immunodeficiency states. Reversal of the immunosuppression is sometimes sufficient to induce tumour regression (withdrawal of cyclosporine in post-transplant lymphoproliferations, highly active anti-retroviral treatment in human immunodeficiency virus related Kaposi's disease). Another line of evidence for the involvement of the immune system in the anti-tumour response comes from the observation of spontaneous anti-tumour responses that parallel the occurrence of paraneoplastic immune-mediated syndromes. Finally, the efficiency of allogeneic transplantation in the haematological field has been clearly demonstrated to depend on the immune-mediated graft vs. leukaemia effect. Nonetheless, tumours develop in immune competent patients because of various tumour escape mechanisms, such as loss of human leucocyte antigen class I antigens, absence of target recognition by deficient adhesion/co-stimulatory molecule expression, tumour cell counterattack against immune effectors, direct (contact-dependent) or indirect (cytokine-mediated) impairment of T-lymphocyte activation. Novel immunotherapy approaches are now orientated in a convergent direction, i.e. the reversal of immune escape mechanisms either via the correction of deficient phases of the immune response or by the amplification of physiological mechanisms.

Non-myeloablative hematopoietic cell transplantation as immunotherapy for hematologic malignancies

Conventional approaches to hematopoietic stem cell transplantation (HSCT) carry risks of morbidity and mortality from regimen-related toxicities, which have restricted the procedure to relatively young patients in good medical condition. This age restriction is unfortunate because the median age of patients with most candidate diseases (e.g., acute and chronic leukemias, myelodysplasia, myeloproliferative diseases, myeloma, and non-Hodgkin lymphoma) for HSCT is greater than 60 years. In non-myeloablative allogeneic HSCT, high-dose cytotoxic therapy as the conceptual basis for treating hematopoietic malignancies has been replaced by graft-versus-tumor effects. The use of potent pre- and postgrafting immunosuppression derived from preclinical studies has allowed omission of myeloablative cytotoxic therapy without compromising hematopoietic donor cell engraftment. This results in a marked reduction in transplant-related toxicities which makes older or medically infirm patients candidates for this treatment option. Initial results in patients with a variety of hematologic malignancies have been encouraging, with documented sustained cytogenetic and molecular remissions in a substantial number of sometimes heavily pretreated and previously refractory patients. While patients with hematologic malignancies will likely require conversion to full donor hematopoiesis for long-term disease control, a state of mixed donor/host hematopoietic chimerism might suffice to ‘cure’ the disease phenotypes in various non-malignant diseases. Strategies aimed at inducing donor-specific tolerance and optimizing post-transplant immunosuppression may eventually eliminate the need for pre-transplant total body irradiation which is relevant for minimizing late toxicities.

Nonmyeloablative allogeneic bone marrow transplantation as immunotherapy for hematologic malignancies and metastatic solid tumors in preclinical models.

We previously demonstrated that a combination of mild total lymphoid irradiation (TLI) with selective depletion of the host's donor-reactive cells allows for stable and graft-vs-host disease (GVHD)-free engraftment of allogeneic bone marrow (BM). In this study, we investigated the efficacy of this nonmyeloablative strategy for BM transplantation (BMT) as immunotherapy for minimal residual disease. BALB/c mice inoculated with leukemia (BCL1) or breast carcinoma (4T1) cells were conditioned for BMT with TLI (200 cGy) followed by priming with donor (C57BL/6) BM cells on day 1, and by injection with 200 mg/kg cyclophosphamide on day 2. After conditioning (day 3), recipients were transplanted with BM cells from the same donor. Treated animals were monitored for 230 days for survival, development of leukemia/solid tumor, and GVHD. BMT converted the mice to complete chimeras and prevented development of leukemia in 90% of recipients and locally growing breast carcinoma in 40% of the mice. Immunization of donors of the second BM with 4T1 cells prevented development of breast carcinoma in 80% of 4T1 inoculated mice. Fewer animals treated for malignancy by nonmyeloablative BMT died of GVHD than those treated by myeloablative BMT. However, late GVHD-related mortality in mice treated for leukemia was higher than after nonmyeloablative BMT to naive recipients (p < 0.00001). Infusion of host-type anti-donor immune lymphocytes 8 days after BMT improved the survival of recipients treated for leukemia without affecting engraftment and the graft-vs-leukemia potential of donor BM. Effective eradication of malignant cells can be achieved following allogeneic BMT after nonmyeloablative conditioning.

Advances in immunotherapy of hematologic malignancies: cellular and humoral approaches.

Monoclonal antibodies have become an important modality for cancer therapy. Genetically engineered chimeric and humanized antibodies have demonstrated activity against overt lymphoma and leukemia, as well as minimal residual disease. Radioimmunotherapy in both nonmyeloablative and myeloablative regimens has produced significant responses and also minimized radiation exposure to normal tissues. Targeted alpha-particle therapy offers the possibility of selective tumor cell kill. Antibody-drug conjugates have produced remissions in acute leukemia. Many proteins potentially act as leukemia or lymphoma-specific antigens for major histocompatibility complex-restricted T cell cytotoxicity. These include the idiotype proteins, breakpoint cluster region (bcr)-abl and other fusion oncoproteins, myeloid-specific differentiation antigens and minor histocompatibility antigens. Clinical trials exploiting the new understanding of the T cell immunology are underway.

Immunotherapy of hematologic malignancies and metastatic solid tumors in experimental animals and man.

Following engraftment of donor hematopoietic cells and induction of host-versus-graft tolerance, immunocompetent lymphocytes of donor origin can induce graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects. Engraftment of allogeneic bone marrow cells can be accomplished following non-myeloablative conditioning while possibly controlling graft-versus-host disease (GVHD). GVL and GVT effects may thus be successfully accomplished following non-myeloablative stem cell transplantation (NST) as shown by data derived from experimental animals and man.

Advances in the immunotherapy of hematologic malignancies: cellular and humoral approaches.

Therapy with unconjugated monoclonal antibodies (mAbs) and radiolabeled mAbs has shown activity in patients with B-cell non-Hodgkin's lymphoma and leukemia. Drug-conjugated mAbs are active in relapsed leukemia. Using these new agents with and after chemotherapy induces a high rate of remission, but this needs to be confirmed in randomized, clinical trials. The antitumor effect of allogeneic stem cell transplantation is being explored through the use of donor lymphocyte infusions for patients who have relapse after transplantation. Attempts to maintain antitumor activity without graft-versus-host disease include CD4 lymphocyte infusions, suicide gene-transfected cells, and the use of cloned T cells more specific for the tumor. Transplantation with nonmyeloablative conditioning regimens relying on the graft-versus-tumor effect of allogeneic lymphocytes has shown preliminary success in the treatment of many hematologic malignancies.

Advances in immunotherapy of hematologic malignancies.

The chimeric anti-CD20 antibody rituxamab, as well as radiolabeled anti-CD20 monoclonal antibodies, have demonstrated significant activity against B-cell non-Hodgkin's lymphoma. Idiotype vaccination in remission may prevent relapse in follicular non-Hodgkin's lymphoma. The campath-1H antibody has activity in chronic lymphocytic leukemia, and additional unconjugated, radiolabeled, and drug-conjugated monoclonal antibodies (anti-CD45 and anti-CD33) have shown activity in acute myeloid leukemia. Adoptive cellular therapy is active against posttransplantation relapse and lymphoproliferative disorders in most patients, and complications of graft-versus-host disease may be controlled by suicide gene transfection of the donor lymphocytes.