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The treatment landscape for hematological tumors has been evolving
at a rapid pace.
Immunotherapy has become the fifth pillar
of oncology.
In recent years, deeper studies of the mechanisms underlying the interactions between the immune system and cancer cells have created new and powerful forms of
immunotherapy.
There are many types of hematologic tumors and have many differences from solid tumors
.
These pose challenges, but they are also unique opportunities
for immunotherapy.
In this article, we will give a brief introduction
to immunotherapy for the treatment of hematological tumors.
Why is hematologic malignancy a challenge and a unique opportunity for immunotherapy?
All hematologic malignancies originate from damaged immune cells that are in constant contact with
healthy immune cells in the same microenvironment.
This makes it beneficial for continuous immune surveillance
.All hematologic malignancies are diseases of the primary and secondary lymphoid organs
.
Normal immune cell development and differentiation also occur at the same site
.
Thus, malignant cells can preempt niches belonging to normal immune cells
.Acute leukemia arises from hematopoietic stem cells and causes hematopoietic dysfunction, cytopenia, and immunosuppression
.Many hematologic malignancies have a low tumor mutational burden
.Immune cell samples are readily available from blood for modification, cell engineering, and retransfusion
.Many hematologic malignancies have an aura state, which helps to study the role of
immune surveillance.
What are the successful immunotherapy regimens for hematological cancers?
Five immunotherapies have been successful in the treatment of hematologic malignancies (Figure 1): allogeneic hematopoietic stem cell transplantation; monoclonal antibodies and innovatively designed ADCs and bispecific T-cell engager; Targeting B cells: immunomodulatory small molecules; Immune checkpoint inhibitors; CAR T-cell therapy
.
Figure 1.
Immunotherapy for hematological tumors
Allogeneic hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation (AlloHSCT) is the earliest successful tumor immunotherapy
for the treatment of hematologic malignancies.
The first allogeneic hematopoietic stem cell transplant was performed by Dr.
Donnall Thomas in 1968
.
This is still one of
the most effective treatments for hematological tumors today.
It is often referred to as the most blunt weapon for chemodoctors because it destroys the hematopoietic and immune systems
with carpet bombs.
There is an increased use of alternative donor transplantation, as well as improved recurrence-free mortality
through advanced supportive care.
Haploid conjugate donor transplantation using cyclophosphamide after transplantation yields comparable
results to matched unrelated donor transplantation.
These new strategies have revolutionized the field of allogeneic stem cell transplantation
.
Monoclonal antibodies and innovative design
Passive immunotherapy with monoclonal antibody is one of the
most commonly used immunotherapy methods for hematologic malignancies.
Rituximab is the first oncology CD20 monoclonal antibody approved by the FDA for the treatment of B-cell malignancies
.
Since then, a large number of antibodies have been developed to treat hematological tumors
.
Monoclonal antibodies are based on lineage-specific antigen (LSA) or non-LSA (NLSA
).
LSA targets tumor-specific antigens at different stages of the same hematopoietic differentiation lineage, e.
g.
, CD20 in B cells and CD3
in T cells.
NLSA is an antigen that plays an important role in the malignant transformation of cells and is not limited to specific hematopoietic cell lineages
.
They can be oncogenic receptors or glycoproteins such as CD52 for chronic lymphocytic leukemia and SLAMF7 for multiple myeloma
.
The main mechanisms of action of antibodies are ADC, ADCP, CDC, and directly lead to cytotoxicity and apoptosis
.
.
Table 1.
Approved monoclonal antibody-based therapeutic agents for the treatment of hematological tumors
Bispecific T Cell Engagers and NK Cell Engagers
A bispecific antibody is an innovative design that fuses the variable regions of two antibodies together to target two different antigens
.
BiTE is a bispecific antibody with one target being the CD3 antibody that binds to T cells and the other being tumor-associated antigens, such as the CD19 antibody
in ALL.
The binding of BiTE to two targets mediates a cell-lytic synapse
similar to innate immune synapses.
Blinatumomab, CD3xCD19 BiTE, is the only BiTE
approved by the FDA for the treatment of R/R PRE-B-ALL.
Blinatumab had a complete response (CR) rate of 43% in patients with R/R B-ALL and 80%
in patients with minimal residual disease.
Bispecific NK Cell Engagers are bispecific antibodies
against the NK cell receptor CD16.
They are being actively developed and are designed to harness the power of the innate immune system to fight tumors
.
Immune checkpoint inhibitors
Immune checkpoint inhibitors (ICIs), designed to modulate the immune system, have been successfully
treated in a variety of solid tumors, including melanoma, non-small cell lung cancer, kidney cancer, and urothelial cancer.
PD-1/PD-L1 and CTLA-4 are negative modulators of the classical immune system, helping cancer cells evade immune surveillance
.
Currently, their role in hematological tumors is limited to tumors with high PD-L1 expression, including Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).
The therapeutic effect of PD-1 blockade is best
demonstrated in HL patients.
HL's unique immunological environment may play a key role in the success of ICI therapy, including: HL's TME contains malignant Hodgkin Reed-Sternberg cells (less than 1%) and a large number of inflammatory immune cell infiltrates, unlike non-HL TME; Amplified 9p24.
1 (containing JAK2/PDL1/PDL2 sites) induces abnormal overexpression of PD-L1 on malignant cells; EBV infection led to upregulation of PD-L1, and PD-L1 expression levels were higher in EBV-positive HL cases
The table below shows the results
of a milestone trial of approved ICI for the treatment of HL.
Table 2.
Results of a landmark trial of approved ICI for the treatment of HL
Targeting B cells: immunomodulatory small molecules
Small molecule immunomodulatory drugs targeting downstream signaling of B cell receptors through BTK inhibitors, SYK inhibitors, PI3K inhibitors and BCL-2 inhibitors, as well as immunomodulatory imine drugs (thalidomide, lenalidomide, pomalidomide), have also become very promising therapeutic strategies
in immunotherapy.
CART cell therapy
CAR T-cell therapy is one of the most exciting and promising forms of adoptive immunotherapy, known as a living drug or serial killer, which combines the cytotoxicity of T cells with the antigen-binding specificity
of CAR.
CAR T-cell therapy has achieved great success
in hematological tumors.
The table below shows the approved CAR T cell products and milestone test results
.
Table 3.
Approved CAR T cell products and milestone test results
Toxic effects of CAR T-cell therapy include:
Cytokine release syndrome;
Neurotoxicity;
Off-tumor, on-target toxicity: B-cell aplastic anemia and hypogammaglobulinemia;
Post–CAR cytopenia.
The future direction of CAR T-cell therapy
Strategies to improve efficacy: dual antigen targeting by bispecific tandem CAR;
Strategies to improve specificity: switchable suicide gene switch CAR and synthetic splission receptor CAR;
Strategies to reduce immunotoxicity: Detuning and tuning of CAR T cells;
Dasatinib induces reversible inactivation;
Humanized CAR to solve immunogenicity problems;
Universal CAR-T;
"Off-The-Shelf" allogeneic CAR T cells
.TRUCKS.
。Combined strategies
for immune checkpoint inhibitors/allogeneic hematopoietic stem cell transplantation/BiTE.
Problems in immunotherapy and future development directions
How can I expand my immunotherapy options?
How to screen for potential biomarkers that predict and predict immune response?
What is the optimal combination therapy strategy and the appropriate sequence of treatment?
How to effectively reduce off-target and on-target toxicity?
What is the role of the gut microbiota in the immune response?
What are the best surrogate endpoints for immunotherapy clinical trials?
What is the impact of immunotherapy on patients' quality of life?
Summary
The success of immunotherapy in hematological cancers in recent years is exciting, and the future looks promising
.
Combination therapy of multiple immunotherapies is the future direction
.
We look forward to more breakthroughs
in the future.
References
1.
“A.
B.
C.
” of Immunotherapy in Hematological Malignancies.
.
.
Promise and Perils.
2.
Monoclonal antibodies in cancer therapy.
