Cancer Immunotherapies (Test 1)

- CTLA-4 and PD-1

- awaken the immune response to cancer cells as "non-self"

- can treat any kind of cancer, regardless of where in the body it started or the type of tissue from which it developed

Immune Checkpoint Inhibitors (ICI)

- selection of biomarker defined populations

- either tumor type or across a variety of different cancers that share a common molecular abnormality

Clinical trials have shifted from enrolling unselected patients exclusively based on the type of tumor to

- first drug approved as an immune checkpoint inhibitor

- tumor must also have dMMR or MSI-H

- should make it easier for immune cells to find and attack the tumor

pembrolizumab (Keytruda)

- DNA mismatch repair deficiency

- loss of MNR proteins

dMMR

microsatellite instability-high

MSI-H

- tumors that have dMMR have difficulty repairing damage to their DNA

- because repair enzymes are missing or deficient, repeating errors pile up in specific regions of the DNA called microsatellities, making them unstable

- these mutations produce abnormal mRNA and abnormal proteins (neoantigens) that are presented vis MHC-1

How do there molecular alteration occur?

- PD-1 inhibitors

- PDL-1 inhibitors

- CTLA-4 inhibitors

Immune checkpoint inhibitors classes

- cancer immune-editing is the process by which various immune system components protect the host against primary tumor development or enhance tumor escape

- the process is tightly regulated by immune checkpoints controlling either the activation or the inhibition of immune responses

- this causes t-cell exhaustion

- immune checkpoint inhibitors reawaken T-cells by blocking suppressor interactions

What is the tumor doing to the immune checkpoints in the body?

- progressive loss of T-cell function due to prolonged antigens stimulation

- t-cells ignore tumors cells overtime

t-cell exhaustion

- blocking these using monoclonal antibodies unleashes antitumor T-cell activity by promoting increased T-cell activation and proliferation by enhancing their effector functions and by supporting the formation of memory cells

- this leads to the release of cytolytic mediators such as perforin and granzyme tumor killing

PD-1 and PD-L1 blocking

Ipilimumab (Yervoy)

CTLA-4 drugs

- Nivolumab (Opdivo)

- Pembrolizumab (Keytruda)

- Cemiiplimab (Libtayo)

PD-1 drugs

- Atezolizumab (Tecentriq)

- Durvalumab (Imfinzi)

PD-L1 drugs

- hypothyroidism

- pneumonitis

- mycocarditis

- arthralgia

- autoimmune diabetes

PD-1 AEs

- hypophysistis

- rash/dematitis

- enteritis

- colitis

CTLA-4 AEs

- corticosteroids

- infliximab

- vedolizumab

colitis treatment

hormone replacement

hypophysiltis treatment

insulin

diabetes treatment

hormone replacement

hypothyroidism treatment

- corticosteroids

- infliximab or cyclophosphamide

- mycophendlate mofetil or IVIg

pneumonitis treatment

- corticosteroids

- IVIg

- plasmapheresis

myocarditis treatment

- Nivolumab (Opdivo)

- Ipilimab (Yervoy)

What 2 anti-PD-1 and CTLA-4 can be used together for better outcomes?

- genetic engineering of a patients's T-cells to express fusion receptors with defined specificities for tumor associated antigens

- capable of eliciting robust T-cell activation to initiate killing of the target tumor cells

- good outcomes in liquid hematologic cancers

CAR-T cell therapies

- YESCARTA (Axicabtagene ciloleucel) large B-cell lymphoma.

- TECARTUS (Brexucabtagene autoleucel) mantle cell lymphoma (MCL).

- KYMRIAH (Tisagenlecleucel) B-cell precursor acute lymphoblastic leukemia (ALL) and large B-cell lymphoma.

- BREYANZI (lisocabtagene maraleucel) large B-cell lymphoma after two or more lines of systemic therapy.

- ABECMA (Idecabtagene vicleucel) multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

- CARVYKTI (Ciltacabtagene autoleucel) indications same as ABECMA

- Each of the FDA approved CAR-T cell therapies are indicated for relapsed or refractory cancers.

CAR-T cell therapies drugs

- cytokine release syndrome (CRS)

- immune effector cell-associated neurotoxicity syndrome (ICANS)

CAR-T cell therapies AE

- is most common acute adverse event

- Serum IL‐6 levels have been shown to correlate with the severity of CRS

cytokine release syndrome (CRS)

- blockade of IL‐6

- tocilizumab

How do you reverse CRS?

anti‐IL‐6 receptor antibody

tocilizumab MOA

- is the second most common acute toxicity

- presents as a toxic encephalopathy with word‐finding difficulty, aphasia, and confusion

- can progress in more severe cases to depressed level of consciousness, coma, seizures, motor weakness, and cerebral edema.

- ICANS is also completely reversible in most patients and tends to have a self‐limited course.

immune effector cell-associated neurotoxicity syndrome (ICANS)