Immunology Of Cancer
Cancerous cells usefully either self-destruct through intrinsic surveillance or present an antigen which results in cell death from the immune system. This is the Elimination Phase. The Equilibrium Phase is when the tumor cells are being killed at the same rate they are proliferating. Finally, the Escape Phase is when the tumor cells are proliferating faster than the immune system can keep up.
There are a few ways in which tumor cells have been found to avoid the immune system.
- Overwhelm: Out-proliferate the immune response
- Hide: Decrease antigen or MHC Class I or II expression
- Subvert: Immunosuppressive chemokines, cytokines
- Shield: Exclude infiltration by tumor antigen-reactive T cells
- Defend: Deactivate tumor-targeting T cells that attack tumor cells
The primary responding cell is the Natural Killer T-cell. However, NK Cells possess receptors that can further activate or inhibit their response.
SLAMF7 Receptor: Increases immune response via dendritic cells
KIR Receptor: Inhibitory receptor serving as a check to prevent autoimmunity
Two presentations
- Non-inflamed phenotype: Low levels of chemokines, no CD8 T-cell filtration, high levels of immunosuppressive macrophages and fibroblasts. Essentially, no evidence a defense was mounted.
- Inflamed phenotype: Negative immune regulators dominate
Immunotherapy
An activated immune system can target tumor antigens systemically and thereby cure patients with metastatic cancer. The hallmark of effective immunotherapy is a plateau on a Kaplan Meier (survival) curve in patients with advanced cancer.
Tumors tend to insulate themselves with dense layers of immunosuppressive stroma, which makes killing them harder for T-cells. Immunotherapy can "peel back" these layers.
High Dose IL-2 (HD-IL-2)
IL-2 (T-Cell Growth Factor) is a cytokine that stimulates proliferation and activates T-Cells.
Drawbacks
- HD IL-2 is toxic and inconvenient to administer (inpatient)
- IL-2 also activates T-reg cells which inhibit the immune response, limiting its efficacy
The inflamed phenotype responds better to IL-2 and checkpoint modulation therapy.
T-Cell Checkpoint Modulation
Stimulation of excitatory receptors using an Agonist Antibody, and blocking inhibitory receptors using a Blocking Antibody.
Negative regulators
- CTLA-4: Outcompetes binding of dendritic B7 to the T-Cell’s CD28, shutting off the T-Cell.
- PD-1/ PD-L1: PD-1 binding its ligands (PD-L1 & PD-L2) will exhaust the T-Cell. It is expressed by tumor cells. Tumors with greater mutational burdens are more likely to respond to anti-PD-1.
Combined therapy of CTLA-4 and PD-1/PD-L1 suppression is effective as CTLA-4 operates in the systemic periphery on APCs while PD-1 focuses on the tumor microenvironment.
LAG-3 is another negative regulator with some possibility of use for triplet therapy.
Side effects
Over-activation of the immune system can lead to Immune-Related Adverse Events (irAE), or autoimmune reactions. irAEs are treated by administration of systemic corticosteroids or immunosuppressive drugs.
Interestingly, patients with irAEs tend to have better outcomes, as it suggests they are strong responders.
Cancer Vaccines
Increase the tumor’s immunogenicity by administering tumor antigens to the body, thereby allowing the immune system to generate a high frequency of tumor-specific T-Cells.
Adoptive T-Cell Therapy
Overwhelm the tumor with a higher frequency of tumor-specific T-cells.
Tumor-Infiltrating Lymphocytes (TILs): Harvesting T-Cells from the patient’s tumor, activating them ex vivo, expanding them, and then re-infusing them.
Or by harvesting T-Cells from the peripheral blood, transfecting a TCR that recognizes the tumor, and then re-infusing those T-Cells.
Effector Antibodies & Antibody-Drug Conjugates (ADCs)
Design an antibody to a tumor-associated antigen and then link it to a cytotoxic agent that can be released when internalized by a tumor, directly killing it.
Clinical Pearls
Pseudo-Progression
When treating a patient with an immunotherapy, the first CT scan may show a tumor that has grown larger. However, the increased size may actually be caused by immune cells attacking the tumor.
Combination Immunotherapy
Using therapies to improve the effects of immunotherapy is superior to the converse, as immunotherapy is focused on creating cures by eliminating all tumor cells. This can produce Treatment-free Survival (TFS).