Cancer Immunotherapies

immunotherapy

now firmly established itself as a novel pillar of cancer care, from the metastatic stage to the adjuvant and neoadjuvant settings in numerous cancer types

CTLA-4 and PD-1

What T cell immune checkpoints propelled the feild of immuno-oncology into its current era and saw the awarding of the 2018 Nobel Prize in physiology or Medicine?

"non self"

Awakening the immune response to cancer cells as _______ is the key in immunotherapy tx.

tumor-agnostic

tx can be used to tx any kind of cancer, regardless of where in the body it started or the type of tissue from which it developed is now a reality

Pembrolizumab (KEYTRUDA)

-1st drug to be approved in the immune checkpoint inhibitors class

-approved by the FDA to tx adults and children with solid metastatic tumors or that cannot be treated with surgery

-first-line in combo

-used in tumors that MUST also have molecular alterations (sMMR, MSI-H)

neoantigens

new proteins found on the outside of tumor cells due to DNA mutations that should make it easier for immune cells to find and attack the tumor BUT cancer cells over express a code receptor (PD-L1) telling T cells to leave them alone

block the PD-L1 and PD-1 interation to awaken T cells to find the neoantigens in the cancer cells

How do we fix the issue of cancer cells expressing PD-L1 which deters the T cells from identifying neoantigens and killing the tumors?

cancer immuno-editing

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

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

Immune checkpoint inhibitors

-YERVOY (ipilimumab)

-OPDIVO (nivolumab)

-KEYTRUDA (pembrolizumab)

-LIBTAYO (cemiplimab-rwlc)

-TECENTRIQ (atezolizumab)

-IMFINZI (durvalumab)

CTLA-4

Molecular target of Ipilimumab:

PD-1

Molecular target of Nivolumab:

PD-1

Molecular target of Pembrolizumab:

PD-1

Molecular target of Cemiplimab:

PD-L1

Molecular target of Atezolizumab:

PD-L1

Molecular target of Durvalumab:

immune-related AEs for checkpoint inhibitors

-colitis

-hypophysitis

-diabetes mellitus

-hypothyroidism

-pneumonitis

-myocarditis

yes

Are 2 immuno checkpoint inhibitors better than 1?

Autologous Chimeric Antigen Receptor T-cell (CAR-T) Therapy

-entails the genetic engineering of a patient'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

CAR-T therapies

-"-cabtagene"; "-leucel"

-YESCARTA (Axicabtagene ciloleucel)

• TECARTUS (Brexucabtagene autoleucel)

• KYMRIAH (Tisagenlecleucel)

• BREYANZI (lisocabtagene maraleucel)

• ABECMA (Idecabtagene vicleucel)

• CARVYKTI (Ciltacabtagene autoleucel)

CAR-T toxicities and AEs

-cytokine release syndrome (CRS) is most common acute adverse event associated with CAR T‐cell therapy. Serum IL‐6 levels have been shown to correlate with the severity of CRS and blockade of IL‐6 with tocilizumab, an anti‐IL‐6 receptor antibody, can reverse CRS

-Immune effector cell‐associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity observed with CAR T‐cell therapy. presents as a toxic encephalopathy with word‐finding difficulty, aphasia, and confusion but 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.