Vaccine Therapy for Myelodysplastic Syndrome

What Is Myelodysplastic Syndrome?

Myelodysplastic syndromes are a class of tumors in which the bone marrow's immature blood cells fail to develop into mature, healthy blood cells. Certain alterations in the bone marrow and blood cells are used to diagnose various myelodysplastic syndromes. The likelihood of developing a myelodysplastic syndrome is influenced by age and prior radiation or chemotherapy treatment. Feeling fatigued and having trouble breathing are signs and symptoms of myelodysplastic syndrome. Blood and bone marrow examination tests diagnose myelodysplastic disorders. Several circumstances influence the prognosis (healing probability) and available treatments.

What Are the Types of Myelodysplastic Syndrome?

• Refractory anemia.

• Refractory anemia with ring sideroblasts.

• Refractory anemia with excess blasts.

• Refractory cytopenia with multilineage dysplasia.

• Unilineage dysplasia along with resistant cytopenia.

• Unclassifiable myelodysplastic syndrome.

• A solitary del(5q) chromosomal aberration linked to myelodysplastic syndrome.

• CMML, or chronic myelomonocytic leukemia.

How Can Myelodysplastic Syndrome Be Diagnosed?

1. Complete Blood Count (CBC):

A process where a blood sample is taken and examined to look for the following:

• Quantity of platelets and red blood cells.

• The quantity and kind of leukocytes.

• The concentration of the oxygen-carrying protein, hemoglobin, in red blood cells.

• The fraction of red blood cells in the blood sample.

2. Peripheral Blood Smear: A peripheral blood smear is a technique used to examine a blood sample for abnormalities in the quantity, kind, size, and shape of blood cells, as well as for excessive iron levels in the red blood cells.

3. Cytogenetic Analysis: A laboratory examination known as cytogenetic analysis counts the chromosomes in a sample of blood or bone marrow and looks for abnormalities, including excess, damaged, missing, or scrambled chromosomes. Chromosome abnormalities could be an indication of malignancy. Cytogenetic analysis is a useful tool for cancer diagnosis, treatment planning, and monitoring response to therapy.

4. Blood Chemistry Studies: A process wherein a sample of blood is examined to determine the concentrations of specific compounds released into the bloodstream by the body's organs and tissues, such as vitamin B12 and folate. A substance's unexpected concentration—either higher or lower than usual—may indicate a medical condition.

5. Bone Marrow Aspiration and Biopsy: A hollow needle is inserted into the hipbone or breastbone to remove bone marrow, blood, and a small piece of bone. Under a microscope, a pathologist examines the bone marrow, blood, and bone in search of aberrant cells.

The excised tissue sample may be subjected to the following tests:

1. Immunocytochemistry: Immunocytochemistry is a lab test that looks for certain antigens, or markers, in a patient's bone marrow sample by using antibodies. Usually, the antibodies are connected to a luminous dye or an enzyme. The antigen can be seen under a microscope once the enzyme or dye is triggered, which happens when the antibodies attach to the antigen in the patient's cell sample. Testing of this kind is used to distinguish leukemia, myelodysplastic syndromes, and cancer, among other illnesses.

2. Immunotherapy: A laboratory test called immunophenotyping uses antibodies to recognize cancer cells by analyzing the kinds of antigens or surface markers in the cells. Certain kinds of leukemia and other blood illnesses can be diagnosed with this test.

3. Flow Cytometry: Flow cytometry is a lab test that counts the number of cells in a sample, determines the proportion of living cells in a sample, and analyzes the size, shape, and presence of tumor (or other) markers on the surface of the cells. One by one, the fluorescently dyed cells are passed through a light beam after being submerged in a fluid and taken from a patient's bone marrow, blood, or other tissue sample. How the fluorescent dye-stained cells respond to the light beam determines the test results. This test aids in the diagnosis and treatment of various malignancies, including lymphoma and leukemia.

4. Fluorescence in Situ Hybridization (FISH): Fluorescence in situ hybridization, or FISH, is a lab technique that counts or examines genes or chromosomes in cells and tissues. Fluorescent dye-containing DNA fragments are synthesized in a lab and introduced to a patient's cell or tissue sample. These fluorescently labeled DNA fragments light up under a fluorescent microscope when they bind to specific genes or regions of chromosomes in the sample. The FISH test aids in the diagnosis and therapy planning of cancer.

What Are the Peptide Vaccines?

To elicit an immune response in vivo, expressed tumor/ leukemia-associated antigens (TAAs or LAAs) can be synthesized as peptide vaccines. A target for immunogenic, selective, nontoxic, and essential to tumor biology would be ideal for LAA immunotherapy. Peptide vaccination effectiveness is contingent upon several characteristics, such as adjuvant antigenicity, systemic dissemination, peptide length, affinity, and affinity of the peptide, as well as the manner of delivery.

1. Wilms Tumor 1 (WT-1): The WT-1 gene on chromosome 11q13 encodes proteins essential for cell division and proliferation. When WT-1 is present in MDS, it can mediate oncogenesis, is strongly expressed on blasts, and has a negative prognostic effect.

2. Proteinase-3+ Neutrophil Elastase (PR-1): PR-1, an HLA-A2-restricted peptide derived from neutrophil elastase 3 (NE) and protein proteinase-3 (P3), is present in higher amounts in the main granules of myeloid blasts in MDS. HLA-A2-positive MDS patients have been shown to have PR-3-specific immune responses; nevertheless, long-term overexpression may cause immunological tolerance and T-cell anesthesia.

3. Combined WT-1 and PR-1 Vaccine: A clinical trial for individuals with AML/MDS examined using the PR-1 and WT-1 antigen-specific vaccination in combination to improve antigenic targeting.

4. NY-ESO-1: The highly immunogenic family of antigens known as cancer-testis antigens (CTAs) is expressed in solid tumors, but due to promoter hypermethylation, CTAs typically express silently in MDS. Hypomethylating drugs are frequently employed as first-line treatments because of their ability to induce CTA expression, which can be used as an immunotherapeutically, even if their exact mode of action is still unknown. While germline tissue can express CTAs such as NY-ESO-1, these tissues typically do not express MHC-I, allowing CD8+ T-cells to be tumor-specific.

5. Receptor for Hyaluronic Acid-Mediated Motility (RHAMM): Patients with AML, MDS, CML, CLL (chronic lymphocytic leukemia), and MM (multiple myeloma) express the cell surface receptor RHAMM in their tumor cells. This receptor's biological function promotes the production of a cell cycle protein necessary for microtubular stability and cell motility. Cancer cells that exhibit upregulation may spread quickly and increase rapidly.

6. Diphtheria Toxin Fusion Protein: In vitro and in vivo experiments revealed that a new SL-401 (DLT388IL-3) that was created by combining the catalytic and translocation domains of diphtheria toxin (DT388) with interleukin 3 (IL-3) induced immune responses against myeloid stem cells.

What Is the Role of Whole-Cell Vaccines?

In the 1990s, preclinical research showed that while irradiation tumor cells could not produce anti-tumor immunity, they may induce a durable immune response against cancer when they were engineered to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF). Taking advantage of these discoveries, gene-transduced tumor cell vaccines (GVAX) are derived from entire tumor cells obtained from patients, which are then grown with granulocyte colony-stimulating factor (G-CSF) and then transduced using an adenoviral vector that codes for GM-CSF. Then, before being delivered autologously to initiate both innate and adaptive immune responses, the tumor cell product is exposed to radiation to stop its multiplication.

The two main advantages of whole-cell vaccines are the ability to target many genes and a simpler production method. But thus far, response rates have been minimal, and they may cause off-target toxicity.

What Is the Role of the Dendritic Cell Vaccine?

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play a crucial role in the innate response. They interact with MHC (I and II) molecules to initiate adaptive immune responses and promote local inflammation. These immune cells can be generated ex vivo from leukemia-derived dendritic cells (DCleu) after leukapheresis, CD34+ hematopoietic progenitor cells, or allogeneic or autologous monocytes. Immunomodulatory drugs were used to start the in vivo conversion of leukemic blasts to DCleu, as suggested by Ambregner et al. Before a patient is reinfused, DCs can be loaded with nucleic acids, viral vectors, or peptides from apoptotic tumor bodies to express tumor targets on MHC-I/II. Prior in vitro research demonstrated that dendritic cells in MDS may present antigens and elicit T-cell responses, confirming their potential utility in treating hematological malignancies.

How Does Nanovaccine Work?

Nanotechnology advances have shown several intriguing uses for nanoparticles, such as improving the immunogenicity and delivery of cancer vaccines. A novel concept tested in vivo is a nano vaccine coated in cell membranes. This comprises a nanoparticle core encased in a cancer cell membrane high in antigens. The method has shown a strong clinical response when used to increase the immunotherapeutic impact of immune checkpoint inhibitors in breast cancer patients. This is a practical alternative for MDS since bone marrow aspirates can easily yield malignant blasts, the source of antigen-loaded cancer cells. To improve the effectiveness of this multi-antigen and customized vaccination, Johnson et al. effectively produced AML cell membrane-coated nanoparticles (AMCNP), in which the NP core was bundled with CpG oligodeoxynucleotides. In mouse models, this vaccination produced a notably higher T-cell response than a control vaccine.

Conclusion

Although strong immune responses have been induced, therapeutic vaccinations for MDS have generally demonstrated acceptable safety profiles; consistent, substantial clinical responses have not yet been seen. For a vaccination to be effective, there must be a strong cytotoxic immune response that can destroy stem cells. In MDS patients, where DCs may be intrinsically defective with decreased precursor frequencies, effective APCs may not be sufficient to elicit robust immune responses. It is necessary to go past this big barrier.