In this discussion, we will go over the applications of immunotherapy in cancer, the immunotherapy agents, and the future direction of chemotherapy.
Introduction to Immunotherapies in Cancer
The primary difference between monoclonal antibodies and immunotherapies is that monoclonal antibodies flag down cancer cells and immunotherapies focus on the immune system itself.
These agents can be interferons, interleukins, antibodies, or immunomodulatory. They do not have a specific target, but they target the whole body system and try to ramp up the immune system.
Because they ramp up the immune system, the immune cells become very effective in destroying anything they see as foreign. This leads to autoimmune-like adverse effects that are seen across most of these agents.
Some cancers, such as kidney and melanoma, have high sensitivity to normal immune processes, and once the immune system ramped up, they can regress on their own.
When the cancer regress on their without any chemotherapy, it is referred to as spontaneous regression. This is very uncommon and is only seen in less than 5% of cases.
Interferons – “Flu and Depression”
Agents: Interferon alfa-2b and pegylated interferon alfa-2b (longer acting)
These are natural proteins that are produced in response to viral infections. They enhance phagocytosis and augment the cytotoxicity of lymphocytes.
Class ADRs: Flu-like symptoms and depression. Patients should always be started on antidepressants right away.
Interleukins – “Narrow Therapeutic Index”
Agents: Interleukin-2 and Denileukin Diftitox
These are naturally occurring cytokines. They are used in renal cancer and melanoma.
Class ADRs: They have a narrow therapeutic index and can be very toxic. Some of the symptoms of toxicity are arrhythmias and capillary leak syndrome.
Checkpoint Inhibitors
There are two main classes of checkpoint inhibitors: CTLA-4 inhibitors and PD1 inhibitors. They each target one of the checkpoints of the immune system that turn the immune system on and off. It is important to note that these checkpoints are how we prevent autoimmune diseases and develop immune resistance.
Cytotoxic T-Lymphocyte-Associated Protein (CTLA-4) Inhibitors – “The First Checkpoint”
Agents:
- Ipilumumab (Yervoy) – Ipi (prefix) + lu (immune?) + u (human) + mab
- Tremelimumab-actl – Tremli (prefix) + li (immune) + u (human) + mab
CTLA-4 is the first checkpoint that occupies the lymph nodes. Normally, CTLA4 will bind to T-cells that recognized self (autoimmune) and kill off those T-cells. Some cancer cells exploit this system and kill off T-cells primed for cancer cells.
CTLA-4 inhibitors bind to CTLA-4 and allow T-cells primed for cancer cells to slip out of lymph nodes and do their jobs.
The problem is this also turns CTLA-4 for all self-targeted T-cells, and the immune system cannot detect the autoimmune system. This leads to fatal immune reactions (enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy).
Programmed Cell Death Protein (PD1) Inhibitors – “The Second Checkpoint”
Agents:
- Nivolumab (Opdivo) – Nivo (prefix) + l (immune) + u (human) + mab
- Pembrolizumab (Keytruda) – Pembro (prefix) + li (immune) + zu (humanized) + mab
- Cemiplimab -rwlc – Cemip (prefix) + li (immune) + mab
- Dostarlimab-gxly – Dostar (prefix) + li (immune) + mab
- Atezolizumab – Atezo (prefix) + li (immune) + zu (humanized) + mab
- Durvalumab – Durva (prefix) + l (immune) + u (human) + mab
- Avelumab – Ave (prefix) + l (immune) + u (human) + mab
PD1 is the second checkpoint that is spread in the general tissue. They have the same function as CTLA-4. Because they have similar mechanisms, PD1 inhibitors have similar ADRs as CTLA-4 inhibitors, but they are not as bad because this is in generalized tissues. Immune-mediated reactions are best treated with corticosteroids.
Immunomodulatory Drugs (IMiDs) – “Flipper babies and ASA81”
Agents: Lenalidomide, thalidomide, and pomalidomide
The mechanism of action for these agents is unknown, but they are thought to cause immune modulation by increasing T-help cells activity, TNF-alpha, and have anti-angiogenesis effects.
They have severe teratogenicity, leading to BBW warnings. This may be due to fibroblast growth factor inhibition. The consequence is flipper babies from inappropriate limb growths.
They can also cause thromboembolic events, and patients must be on antithrombotic treatment. The most common is aspirin 81mg but may have to elevate to DOACs or enoxaparin if not sufficient.
Other side effects include somnolence (worst with thalidomide) and peripheral neuropathies (also worst with thalidomide).
Bi-Specific T-Cell Engager (BiTE)
These are the upcoming agents: Blinatumomab, Teclitamab-cqyv, and mosunetuzumab-axgb
They are antibodies with one arm that binds to CD and the other that binds to the cancer target. Ultimately, they force T-cells to the target.
The main problem with these agents is cytokine release syndrome due to the severe dumping of cytokines because the cells are killed off so quickly. Patients on these therapies should be admitted for monitoring. Severe neurotoxicity is the other standout ADR.
Chimeric Antigen Receptor T-Cells (CAR-T Cell)
This is an interesting concept where the patient’s own T-cells are collected, modified in the lab to express the desired CAR-T receptor, grew them, and inject back into the patients.
The goal of this therapy is long-lasting immunity.
The problem with this therapy is the cytokine release syndrome and tumor lysis.
The most common targets are CD19 (the most common) and BCMA for myeloma.
It is a one-time treatment, costing over half a million dollars.
The Future – Vaccine and Gene Therapy
First “vaccine” for melanoma: Talimogene. This is an injectable that utilizes the herpes virus that lyzes in the body, releasing factors that the body can build a defense against.
Nadafaragene firadenovec-vncg, is a new kind of gene therapy that is instilled into the bladder with an adenovirus vector. It kills off tumor cells there.