The Role of Immunotherapy in Hematologic Malignancies - An Overview

Introduction

The body naturally uses the immune system to identify and eradicate cancer cells, known as cancer immunosurveillance. Through a process known as immunological editing, cancer cells can occasionally avoid this observation, allowing them to lie dormant until eventually resurfacing. Additionally, cancer cells employ various techniques to weaken the immune system so they can continue to exist and increase.

Hematologic malignancies (blood cancer), which include leukemia, lymphoma, multiple myeloma, and associated illnesses, are tumors that start in the blood and lymphatic systems. Due to their distinct features, these tumors are good candidates for immunotherapy, a cutting-edge method of treating cancer that harnesses the body's immune system to combat the disease. Cancer treatment has changed due to immunotherapies encouraging outcomes in treating hematologic malignancies.

What Is the History of Immunotherapy in Hematologic Malignancies?

Immunotherapy mainly uses immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, targeted antibodies, and stem cell transplants for treating blood malignancies. An important turning point in the history of immunotherapy for blood malignancies was the 1968 invention of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which offered a potential treatment for illnesses like lymphoma and leukemia.

Novel techniques for immunotherapy emerged in the second part of the 20th century. In 1997, the FDA (Food and Drug Administration) approved Rituximab, a monoclonal antibody that targets CD20, as the first cancer treatment. Other monoclonal antibodies that target distinct markers on cancer cells, such as Tafasitamab, Daratumumab, and Lintuzumab, were made possible thanks to its foundation. Bispecific antibodies like Blinatumomab may arise due to these antibodies' potential loss of efficacy in relapsed (indicating a return of the disease after initial response) or refractory (an event in which a disease does not respond to treatment or ceases to respond to it) cases.

ADCs, or antibody-drug conjugates, have been licensed to treat some blood malignancies. One example is Brentuximab vedotin—additionally, tumor vaccines such as the WT1 peptide-based vaccination were developed. Acute myeloid leukemia and Hodgkin lymphoma have been successfully treated with immune checkpoint inhibitors (ICIs), particularly PD-1 or PD-L1 inhibitors. B-cell lymphomas, particularly Hodgkin lymphoma, have also responded well to CTLA-4 inhibitor treatment.

CAR-T, or adoptive cell therapy (ACT), has become more popular. Since its initial administration in 2008 for B-cell lymphoma, CAR-T therapy has demonstrated exceptional efficacy in treating a variety of blood malignancies, leading to prolonged remissions. Significant clinical trials and FDA approvals, such as Axicabtagene ciloleucel and Tisagenlecleucel in 2017, have accelerated the development of CAR-T therapies. In patients with relapsed or resistant cases of acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), CAR-T treatment is currently showing promising outcomes.

What Are the Challenges and Advancements in Hematologic Malignancy Immunotherapies?

Malignancies that arise in cells that make blood are known as hematologic malignancies. Hematopoietic cells' genetic and epigenetic modifications cause these malignancies. Hematologic malignancies are classified according to the kind of blood cell impacted and the location of the malignancy.

• Acute Myeloid Leukemia (AML): Immature myeloid progenitor cells build up in the bone marrow and blood in acute myeloid leukemia (AML). Somatic mutations in hematopoietic stem and progenitor cells (HSPCs) are frequently linked to it. KIT, RUNX1, CEBPA, TP53, NRAS, PTPN11, NF1, GATA2, FLT3, DNMT3A, TET2, IDH1/2, MLL, and PRMT are among the genes often mutated in AML. Therapeutic targeting of leukemia stem cells (LSCs), implicated in the genesis of AML, is being investigated. Due to the shortcomings of current AML treatments, such as allogeneic hematopoietic stem cell transplantation, immunotherapies are being investigated as less harmful and more successful options.

• Immunotherapy for AML: The heterogeneity of AML cells makes it difficult for the immune system to identify markers particular to the tumor, which makes developing immunotherapy for AML problematic. AML cells can express inhibitory immunological checkpoints, including PD-L1, PD-L2, CD47, and CD70, and suppress natural killer cells to avoid immune responses. Immunotherapies trials, such as those involving anti-PD1 or anti-CTLA4 therapy, are promising, particularly when eradicating detectable residual illness. In AML, CD27, CD123, FLT3, CLL-1, CD47, and IL-1 receptor accessory proteins are additional targets for immunotherapy. Many strategies are being investigated, including antibody-drug conjugates (ADCs) and bispecific T cell engagers (BiTEs). CAR-T cell treatments are also being developed to target CD33, CD123, and other antigens. Personalized dendritic cell vaccines and natural killer (NK) cells are two adoptive cell transfer techniques considered possible AML therapies.

• Myeloproliferative Neoplasm (MPN): MPNs are bone marrow-derived blood cancers. They include MPN, unclassifiable, polycythemia vera (PV), required thrombocythemia (ET), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Immunotherapies, particularly interferon-alpha (IFN-alpha), are being investigated for treating MPNs. PD-L1 can be upregulated by JAK2 mutations in PMF, indicating a possible advantage of PD-1 inhibition. Neoantigens linked to MPL, CALR, and JAK2 mutations may trigger T-cell responses unique to tumors. Nonetheless, there is still a need to determine how well immunotherapies work for MPNs, especially those resistant to JAK2 inhibitors.

• Hodgkin's lymphoma (HL): Relating to aberrant amplification of chromosome 9p24.1, which contains JAK2, PD-L1, and PD-L2, Hodgkin's lymphoma accounts for ten percent of instances of lymphoma. PD-1 inhibitors have demonstrated effectiveness in treating relapsed or refractory HL, such as Pembrolizumab and Nivolumab. Antibodies directed against CD30, such as Brentuximab vedotin, target RS cells, which indicate HL. Complete remission rates are higher in combination therapy incorporating Brentuximab vedotin and PD-1 inhibitors.

• Non-Hodgkin's Lymphoma (NHL): There are several forms of NHL, such as mantle cell lymphoma (MCL), marginal zone B cell lymphoma (MZL), small lymphocytic lymphoma (SLL/CLL), follicular lymphoma (FL), and diffuse large B cell lymphoma (DLBCL). In DLBCL and FL, PD-1 inhibition is not as effective, perhaps because of a "cold" tumor microenvironment. Nonetheless, some NHL subtypes show beneficial responses, such as EBV-positive patients. With medications like Tisagenlecleucel and Axicabtagene ciloleucel receiving FDA approval for B cell ALL and DLBCL, CD19 CAR-T cell treatments have proven beneficial.

• Multiple Myeloma (MM): In multiple myeloma, plasma cells in the bone marrow grow clonally. There are difficulties with MM immunotherapies, as PD-1 blocking has a restricted therapeutic window. ADCs that target BCMA, such as Belantamab mafodotin, have received approval. Promising CAR-T cell treatments target CD44v6, SLAMF7, and BCMA. Even though several trials combining anti-PD-1 and anti-CD38 antibodies have encountered difficulties, the current research investigates new approaches to enhancing CAR-T cell efficacy and overcoming roadblocks in treating multiple myeloma.

What Are the New Approaches for Treating Blood Cancers Effectively?

More novel and exciting therapeutic modalities exist for hematologic malignancies or blood cancers.

1. New Immune Checkpoint Targets:

• Targets on T or NK (Natural Killer) Cells:

  • NK Cells: These immune cells can combat cancerous cells. Certain medications may increase their activity.

  • Receptors: These cells include receptors that, when blocked, increase their capacity to eradicate malignancy. Particularly in the cases of multiple myeloma and head and neck cancer, drugs that target these receptors show promise.

• Targets on Macrophages Associated With Tumors:

  • Macrophages: Cancer cells send signals to macrophages, instructing them not to "eat" them. Macrophages can destroy cancer cells by blocking these signals.

  • CD47: A cancer cell signal that, when inhibited, aids in removing lymphoma cells by macrophages. Positive responses have been seen in clinical trials when CD47 blockers are combined with other medications.

• New Prospects for Immune Checkpoint Inhibition:

  • New Checkpoints: Researchers are finding new checkpoints that can strengthen the immune system's defenses against cancer when they are blocked.

  • Examples: The potential of CD32A, CD96, CD105, and CD200 in immunotherapy against blood malignancies is being investigated.

2. Innovative Methods for CAR-T Cell Therapy:

• CAR-T Cells: These immune cells are tailored to target cancer cells specifically.

• CD22: A target for CAR-T cells, particularly when CD19 CAR-T therapy is unsuccessful because cancer cells have lost their CD19.

• Combination Treatments: Employ CAR-T cells to target several antigens simultaneously for more successful treatment.

• Examples: CAR-T cells directed against CD38, CD56, and GPRC5D, as well as CAR-T cells for multiple myeloma and NY-ESO-1.

3. Cancer Vaccinations:

• WT1 and Proteinase 3: Peptide vaccines that stimulate the immune system to combat AML by targeting particular antigens on leukemia cells.

• DC Vaccines: Vaccines made from antigens linked to leukemia, albeit their efficacy is currently restricted.

These methods offer fresh ways to strengthen the body's defenses against cancer cells and present promising new avenues for treating blood malignancies.

Conclusion

It is anticipated that immunotherapies for some blood malignancies will become widely used in the next few years, bolstered by remarkable success stories like the successful treatment of B-ALL and DLBCL with CAR-T cells. Individual responses can differ even with these advances, highlighting the significance of biomarkers in guiding tailored treatment decisions. The effectiveness of PD-1 immune checkpoint inhibitors (ICIs) highlights the necessity of discovering biomarkers to assess treatment efficacy. An increasing number of patients require novel immunotherapies and gene/cell therapies, such as universal CAR-T cells, to treat a wide range of blood malignancies since these diseases are more common in the elderly due to aging populations in many nations. New immunotherapies like BiTEs, TriKEs, CAR-T, CAR-NK, and ADCs may be developed using monoclonal antibodies (mAbs) and conventional chemotherapy. Overall, a growing range of immunotherapy strategies for blood malignancies is anticipated to develop future treatments that are safer, more accurate, and more successful.