Checkpoint Inhibitors

T-cell activities or partly regulated by a balance of checkpoint inhibitory and activating signals.

Immune checkpoints are part of the natural balance of the immune system to prevent autoimmunity and are exploited by cancer cells to suppress the immune response.

PD-1 receptor is expressed mostly in mature cytotoxic T lymphocytes as well as within the tumor microenvironment.

Cancer cells express the programmed cell death ligand PD-L1 or PD-L2.

The PD-1  pathway is initiated by contact withPD-L1 or PD-L2 ligands.

Functionally this causes an off signal for apoptotic killing pathways and when the pathway is inhibited or blocked, the cancerous cells can be destroyed.

Immune checkpoint proteins and signals regulate self tolerance, and this prevents the body from attacking itself.

Immune checkpoint inhibitors (ICI) block proteins PD1, PD-L1, and CTLA-4 that allow tumor cells to evade detection and killing by T cells.


A number of checkpoint pathways have been identified: program death 1 (PD-1), cytotoxic TN lymphocyte-associated antigen 4 (CTLA-4), lymphocyte-activating 3 (LAG 3), T cell immunoglobulin and mucin  domain-containing3 (TIM 3), and B and T lymphocytes attenuator.

Tumors may utilize checkpoint inhibitors and activating pathways to suppress T-cell activity and limit antitumor immune response.

Cancer cells’s  take advantage of the natural system to appropriate checkpoint pathways and to escape detection by T cells that have tumor antigen recognition capabilities.

Successful targeting and blockade of checkpoint pathways depend on ligand expression and on multiple intracellular and extracellular mechanisms.

These drugs harness the adaptive immune system to recognize tumor antigens.

Autoimmune like toxicity can occur and affect multiple organs especially the skin, the G.I. tract, and liver and the endocrine system.

Are essential to normal cell function, as they regulate the response to antigen exposure and prevent unbridled autoimmunity.

Immune checkpoints control the amplitude and quality of the body’s T-cell response maintaining self tolerance, prevention of autoimmunity, and suppressing in appropriate responses to host antigens, and protecting non-tumor tissues from damage.

The adaptive immune system recognizes and prevents tumor development by cell mediated T-cell activity, especially through cytotoxic T-cell.

One facet of immune evasion involves the regulation of immune checkpoint pathways, facilitated by ligand-receptor interactions, serving to prevent inflammatory response.

Cytotoxic T lymphocyte associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are immune checkpoint receptors on the surface of immune cells that interact with their respective ligands on tumor cells (CTLA-4 with CD80, CD86 and PD-1 with programmed death ligand 1 (PD-1, PD-2).

Immune checkpoint pathways are exploited by viral infections.

Major targets of immune checkpoint inhibitory pathways include CTLA-4, PD-1, LAG-3.

Checkpoint inhibitors include ipilimumab which blocks CTLA-4, As does tremelimubab, PD-1 and checkpoint inhibitors pembrolizumab and nivolumab.

At least 5 immune checkpoint inhibitors (atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab) received approval.

Findings of a phase 1/II CheckMate 032 study showed an overall response rate of 46% with a combination of nivolumab and ipilimumab.

CTLA-4 blocking antibodies undo T-cell inhibition at the activation step of the antitumor immune response.

PD-1 blocking antibodies undo T-cell Inhibition at the effector step of the antitumor immune response, activating or resurrecting exhausted T cells in the tumor microenvironment.

Chronic exposure to tobacco carcinogens and accumulation of mutations overtime can lead to T-cell exhaustion and trigger T Cells to turn it off and this may be manifested through the upregulation of the programmed death ligand (PD-L1) on tumor cells, which can inhibit T cell function by binding to programmed death 1 (PD-1) on T cells.

The clinical efficacy of checkpoint inhibitors indicates that multiple genetic mutations make such drugs more effective.

Tumors which are highly mutated are often resistant to chemotherapy but are susceptible to check point inhibitors.

Highly mutated tumors produce comparatively more misshapen proteins that can trigger an immune response.

The most heavily mutagenized cancers, the ones least likely to respond to standard kinase based targeted therapies, are most likely to respond to checkpoint inhibitors.

Increased mutategen changes is associated with increased numbers of immunogenic antigens.

The expression PD-L1 and the mutational load correlate with the likelihood of response to immune checkpoint blockade.

Immune checkpoint inhibitors restore the ability of T cells to recognize mutations by blocking the interaction between PD-L1 on tumor cells and PD-1 on T cells.

T cells are been able to activate, and recognize cancer cells as foreign and destroy them.

Patients with MSI-H phenotype or a dMMR immunohistochemistry colorectal cancers seem to derive the most benefit from PD-1/PD-L1 inhibitors.

Approved for the treatment of chemotherapy refractory microsatellite instable-high cancers regardless of the primary tumor site.

Adverse events associated with immunotherapy can occur during treatment, but also after.

The anti-tumor benefit of these agents is tempered by excessive off target inflammation, characterized by the immune related adverse events (irAEs).

Immune related adverse events can involve  any organ, the skin G.I. tract, liver thyroid gland and lungs are the most affected although the less commonly  involved cardiovascular, neurologic systems are associated with high mortality.

Ongoing adverse affects of such agents can be rashes, diarrhea, anorexia, as long as two years after treatment.

The most common immune related adverse events associated with checkpoint inhibitors affect the skin and gastrointestinal tract, although the liver, endocrine system, and other organs can be affected to a lesser degree.

ICI induced pancreatic injury ranges from asymptomatic, hyperlipasemia to symptomatic acute pancreatitis.

Hyperlipipasemia or hyperamylasemis has been observed approximately 1 to 4% of patients receiving ICIs.

Interstitial pneumonitis can be a side effect of TKI- and checkpoint inhibitors can be fatal unless it is diagnosed early and appropriately treated.

Among the first toxicities to appear are those that are skin related.

Skin toxicities include maculopapular rash, vitiligo, and pruritus.

Vitiligo may suggest a better clinical outcome.

In patients with melanoma, vitiligo like symptoms can occur as immunotherapy adverse reaction between 3.4 and 25% of patients during treatment with an immune checkpoint inhibitor.

In adjuvant treatment for stage III melanoma the occurrence of immune related adverse effects was associated with a longer relapse free survival in pembrolizumab arm.

Immune related adverse events are more common with CTLA-4 agents than with PD-1 agents.

GI adverse immune reactions may lead to diarrhea, obstruction, perforation, or toxic megacolon.

CTLA-4 agents are associated with a higher incidence of overall and high-grade immune mediated diarrhea and colitis compared with PD-1/PD-L1 agents.

Combinations of checkpoints inhibitors  are associated with a higher risk of immune mediated colitis.

Hypothyroidism can be permanent after immunotherapy treatment.

Immune related hepatitis may occur.

ICI induced hepatitis is defined as aminotransferase elevations of greater than five times or greater than 20 times the upper limit of normal, respectively, and it is reported to occur in 1 to 2% of patients with ICI monotherapy and 10% of patients receiving combination therapy.

Call Myocarditis a risk with checkpoint Inhibitors occurs early after treatment starts and has malignant course, but responds to high-dose steroids.

Myocarditis in patients receiving immune checkpoint inhibitors, has a median time of onset of 34 days.

Asymptomatic elevation of amylase and lipase may occur.

It occurs more often in patients on combination therapy and in those with diabetes.

94% of myocarditis cases had elevated levels of troponin, a biomarker for acute MI.

Immune-mediated myocarditis may be characterized by fulminant progression.

There is a relationship between the gut microbiota and antibiotics, and the response to checkpoint inhibitors: antibiotics delivered before treatment may diminish benefits in response rates and duration of responses: irrespective of tumor site.

The Chronic pro inflammatory state of obesity increases the benefits of immune checkpoint inhibitor therapy both in melanoma and in advanced renal cell cancer.

Thoracic radiation  in patients  with prior immune checkpoint inhibitor therapy was associated with a very high risk of toxicity and significant and persistent radiation pneumonitis.

Endocrinopathies are among the most frequent immune related adverse effects.

The clinical consequences of checkpoint inhibitor endocrinopathy results from hormone deficiency, which is usually permanent.

Thyroiditis is the most common endocrinopathy affecting 20 to 30% of patients treated with immune checkpoint inhibitors.

Some patients who develop thyroid dysfunction or adrenal dysfunction from checkpoint inhibition may need to take medication for these conditions for the rest of the life.

Thyroiditis manifest initially as thyrotoxicosis, which is followed by hypothyroidism.

The occurrence of certain dermatologic, endocrine, and G.I. immune related adverse events may be associated with a higher likelihood of improved overall survival in patients with lung, melanoma, or genitourinary cancers.

Some common endocrine side effects of immune checkpoint inhibitors:

1. Thyroid dysfunction: including both an overactive (hyperthyroidism) and underactive (hypothyroidism) thyroid gland. 

2. Adrenal insufficiency:ICIs can cause inflammation of the adrenal glands, leading to adrenal insufficiency. 

3. Hypophysitis: ICIs can cause inflammation of the pituitary gland, leading to hypophysitis.

4. Diabetes mellitus: ICIs can cause insulin deficiency or insulin resistance, leading to the development of diabetes mellitus.

5. Gonadal dysfunction: ICIs can interfere with normal hormone production in the ovaries or testes, leading to gonadal dysfunction.

Overall survival, however, is not improved in patients experiencing a hepatobiliary, pulmonary, or high grade immune adverse events.

There are subsets of patients who are less responsive to immune checkpoint inhibitor based therapy including: patients with a low mutation burden reducing the likelihood that cognate  cytotoxic T lymphocytes (CTLs) recognize a suitable neo epitope target expressed by cancer cells, interference and gamma pathway abnormalities resulting in impaired killing of cancer cells by cognate CTLs, or alterations in the human leukocyte antigen (HLA) class I heavy chain or beta2 microglobulin, thE HLA class I subunits mediating tumor antigen presentation resulting in the escape  of cancer cells  from elimination by CTLs.

HLA proteins display peptides from inside the cell to help immune cells find cancerous or infected cells.

A specific form of a gene that may make immune checkpoint inhibitors less effective for some people. 

The gene form is HLA-A*03, is found in 2% to 16% of the US population.

Patients with HLA-A*03 died sooner after immune checkpoint inhibitor treatment than people with other forms of the HLA-A gene. 

This pattern persists for different immune checkpoint inhibitors and different types of cancer, including kidney, bladder, and skin cancer.

HLA-A is a member of a set of genes—including HLA-B and HLA-C—that help the immune system find and destroy cells that are cancerous or infected with a virus or bacteria.

HLA genes make proteins called human leukocyte antigens (HLA), which take bits and pieces of proteins from inside the cell and display them on the cell’s surface. If the cell is cancerous or infected, the HLA proteins display abnormal fragments that trigger immune cells to destroy that cell and any others displaying the same fragment.

A*03, for instance, is one of more than 2,000 alleles of HLA-A. 

That natural variation in HLA genes is, in part, what makes some people more susceptible than others to certain viral infections and autoimmune diseases. 

HLA*03 is the only allele that works as a marker of treatment response for multiple types of cancer and different immune checkpoint inhibitors: 

People with A*03 benefit less from immunotherapy.

Among various HLA alleles, HLA-A*03 emerged as the strongest biomarker of immune checkpoint inhibitor effectiveness. 

People with A*03, regardless of what kind of cancer they have died nearly 1.5 times sooner after starting treatment than those with a different allele.

A*03 was linked with a shorter time to death for people with bladder, brain, melanoma, lung, and kidney cancer. However, the impact of having A*03 was greatest in people with kidney cancer. 

Among participants of four clinical studies who received an immune checkpoint inhibitor for kidney cancer, those with A*03 didn’t live as long before their kidney cancer grew back or they died, compared with those who didn’t have the allele.

The link between A*03 and immune checkpoint inhibitor effectiveness held true regardless of a person’s age, sex, ancestry, the type of immune checkpoint inhibitor they took, and whether they got chemotherapy at the same time.

There are some people with A*03 for whom immune checkpoint inhibitor treatment worked. 

HLA-A3 (A3) is a human leukocyte antigen serotype within HLA-A serotype group. 

The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. 

For A3, the alpha, “A”, chain are encoded by the HLA-A*03 allele group and the β-chain are encoded by B2M locus.

This group currently is dominated by A*0301. 

A3 and A*03 are almost synonymous in meaning. 

A3 is more common in Europe, it is part of the longest known multigene haplotype, A3-B7-DR15-DQ6.

A3 is primarily composed of A*0301 and *0302 which serotype well with anti-A3 antibodies. 

There are 26 non-synonymous variants of A*03, 4 nulls, and 22 protein variants.

A3 serotype is a secondary risk factor for myasthenia gravis and lower CD8+ levels in hemochromatosis patients.

The HFE (Hemochromatosis) locus lies between A3 and B7 within the A3::DQ6 superhaplotype.

Many patients with grade 1 to 2 irAEs  can be managed with topical steroids, hormone replacement, and I was holding ICI therapy.

Approximately 20 to 50% of patients treated with ICI‘s will experience grade 3 to 4 irAEs, which may require high dose oral or Intravenous steroids and cessation of ICI therapy.

if IRA is symptoms persist despite systemic steroids addition of immunosuppressive agent including infliximab mycophenolate mofetil or vedolizumab is recommended.

Loss of Interferon gamma signaling is associated with resistance to checkpoint inhibitors.




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