Cancer Immunotherapy for Leukemia

Cancer Immunotherapy for leukemia: Hot Molecules

Cancer Immunotherapy for leukemia: Review

Leukemia can be divided into lymphoblastic leukemia and myeloid leukemia.
Cancer immunotherapy for lymphatic leukemia
Cellular Approaches
The response rates of acute lymphatic leukemia to DLI are inferior compared to other haematological cancer types and mostly lower than 15 %. An alternative to conventional T cells for adoptive immunotherapy is the application of genetically modifi ed T cells. However, its use in haematological malignancies was limited due to the antigen restriction of the T-cell clone. A possibility to avoid the limitations of TCR gene transfer may be the use of chimeric antigen receptors (CARs). Ongoing phase I trials are investigating the benefit of CAR-modifi ed T cells in the context of acute lymphatic leukemia (NCT01044069 and NCT01029366).
Up to now, NK cell alloreactivity does not seem to be benefi cial in the treatment of acute lymphatic leukemia, but some reports with genetic modifi ed NK cells provide some encouraging data. Retroviral or electroporation of NK cells to induce a CD19 targeting CAR led to increased NK cell-mediated killing of acute lymphatic leukemia cell lines, as well as primary acute lymphatic leukemia blasts.

CD20 Antibodies: Rituximab is a chimeric mouse/humane antibody that has dramatically changed the therapy of NHL. Since CD20 is also expressed in B-acute lymphatic leukemia cells, the antibodies have also been used in the acute lymphatic leukemia setting. Reports have shown that the addition of CD20 antibodies to conventional chemotherapy leads to a higher rate of complete response as well as a better overall survival. Of note the advantage seems only to be true in younger acute lymphatic leukemia patients.
CD22 Antibody: Inotuzumab ozogamicin is an anti-CD22 antibody linked to calicheamicin. Calicheamicin is a toxic antibiotic which causes double-strand breaks in the DNA. In a fi rst phase II trial of nearly 60 patients, 57 % responded to the immunotoxin and showed an OS of 5.1 months. Epratuzumab is an unconjugated CD22 antibody. In a very small study with 15 paediatric patients, nine achieved CR with only moderate toxicity. Furthermore, the addition of epratuzumab to standard chemotherapy improved the CR rate in a Children's Oncology Group (COG) study. Moxetumomab pasudotox is a newgeneration toxin-linked anti-CD22 antibody that is currently being investigated in a phase I trial.
CD52 Antibody: CD52 is a glycoprotein on the surface of lymphoid cells. CD52 can be found on T and B cells, making the antigen interesting for application in T- and B-acute lymphatic leukemia. Campath-1H is a humanised IgG1k antibody that showed major efficiency in
NHL and CLL.
CD19 Antibody: The GMALL showed data on 21 patients who achieved MRD negativity after blinatumomab (a structured monoclonal antibody combining two single-chain antibodies to CD19 B cells and to CD3 T cells) therapy. The response rate was 80 % with a probability of relapse-free survival of 78 % and only mild side effects.
Cancer immunotherapy for Myeloid Leukemia
Peptide Vaccination: Known immunodominant and HLA-A2 (being highly prevalent among Caucasians)-binding nonamer peptide epitopes of WT1 and proteinase 3 (PR1) are most widely researched and developed as peptide vaccines for acute Myeloid leukemia in clinical trials.
Receptor for hyaluronan-mediated motility (RHAMM) has also been targeted in vaccine trials. Vaccines have been combined with adjuvants such as montanide or keyhole limpet hemocyanin (KLH), with or without concurrently administered granulocyte-macrophage colony- stimulating factor (GM-CSF). As these studies comprise small and diverse groups of patients treated with different vaccines and schedules, it is diffi cult to draw meaningful conclusions about the true effi cacy of peptide vaccination in acute Myeloid leukemia.
Dendritic Cell Vaccination:
DCs pulsed with leukemic cell lysates, apoptotic leukemic cells, or modified WT1 peptides have been successfully explored in small clinical trials.
In 2010, a phase I/II clinical trial ( ID: NCT00834002) investigated the effect of vaccination with full-length WT1 mRNA-electroporated autologous dendritic cells in ten patients with acute Myeloid leukemia, and in five of them, a molecular remission was reached, although not always persisting.
Stripecke and colleagues recently developed a tricistronic lentiviral vector co-expressing a truncated form of WT1, granulocyte- macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4), which was used for the transduction of human monocytes, leading to very rapid self-differentiation of these cells into "SmartDC/tWT1" that showed very promising potential for the use as immunotherapy against WT1-expressing tumors.

Monoclonal Antibodies
Anti-CD33 (present on 90 % of acute Myeloid leukemia cells) mAbs are the most widely studied and have proven both clinical efficacy and important toxicity. Current promising trials combine anti-CD33 mAbs in more fractionated (less toxic) administration with chemotherapy. Also radioisotope-coupled anti-CD45 antibodies have been used as part of the conditioning before allo-HSCT. Alternative mAb tools include antibodies that block the immune-regulatory effect of molecules, such as cytotoxic T lymphocyte antigen-4 (CTLA4) or programmed cell death-1 (PD-1), and thereby unleash cytotoxic T lymphocyte function.

Adoptive T Cell Transfer
A promising immunotherapeutic strategy,using PBMC transduced with a CAR, a constructthat encodes the VH and VL domain of a tumorantigen-specifi c antibody coupled to the CD3ζchain (alone or combined with the signaling motifs of CD28 or CD137 to enhance the signal)of a TCR, has not yet been evaluated in clinical trials of acute Myeloid leukemia.

Adoptive NK Cell Transfer
In WT1-DC vaccination and KIR-mismatched haploidentical HSCT. Especially in the context of haploidentical HSCT, NK cell adoptive therapy is currently being explored in clinical trials (NCT 00799799, NTR 2818).
More and more effective methods are on the way.

Cancer Immunotherapy for leukemia: Reference

Stübig T, et al. Immunopathology and Immunotherapy of Lymphoblastic Leukaemia[M]//Cancer Immunology. Springer Berlin Heidelberg, 2015: 105-116.
Snauwaert S et al. Immunopathology and Immunotherapy of Myeloid Leukemia[M]//Cancer Immunology. Springer Berlin Heidelberg, 2015: 93-104.