Drugs used in oncology

Drugs used in oncology

Malignant disorders, also called cancers, are an important group of disorders. They constitute a substantial proportion of non-communicable diseases and affect all regions of the world. Cancers, such as of prostate, lung, colon and breast are an important cause of high mortality despite heavy cost. Although with advancement in medical sciences, better treatment options are being devised leading to improved survival rates among patients but their morbidity and mortality still remains high. There are a number of challenges while treating cancers, such as, disease stage at the time of diagnosis, disease behavior, patient characteristics, limited treatment options, expensive treatment, resistance to treatment, potentially lethal adverse effects and disease recurrence. Topics in this module include the drugs used in treating cancer including their mechanisms of action and adverse effects, and general principles of their use.

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Immuno-oncology

Immune Checkpoint inhibitors

Immune checkpoint (IC) proteins are regulators of inhibitory signalling pathways that are essential for homeostasis of the T cell-mediated immune response. Immune checkpoint inhibitors are (generally) monoclonal antibodies that are used as a type of cancer immunotherapy and that act to re-establish immune detection and T cell-directed attack on tumours. Whilst these agents can be highly effective, they do not work for every patient, with certain cancers being inherently resistant to this pharmacological approach. Therapy-induced resistance to these agents can develop.  Barrueto et al. (2020) provide an extensive review of the immune checkpoints, and the molecular mechanisms that can lead to resistance (PMID: 32114384).

The image below is a simplified diagram of the ICs that are targeted by currently approved monoclonal antibodies. It focuses on the communications between tumour cells and T cells, but does not include T cell receptors and other accessory proteins that may be components of the functional checkpoint complexes.

Adapted from “Cell Immunotherapy (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

The PD-1/PD-L1 checkpoint

PD-1 (programmed cell death 1, a.k.a. PDCD1 or CD279) is a transmembrane protein on immune cells that interacts with the membrane-bound ligand PD-L1 (PD-1 ligand 1, or CD274). The PD-1/PD-L1 interaction is a key inhibitory checkpoint in T cell activation. Some cancers aberrantly express PD-L1 which allows them to evade immune surveillance and disrupts T cell-mediated anti-tumour immunity.

Therapeutic monoclonal antibodies have been developed to target either PD-1 or PD-L1 to correct the immunosuppressive effect of PD-1/PD-L1 pathway signalling within the tumour microenvironment, and to re-initiate T cell killing of tumour cells.

Approved antibodies (May 2022)

Antibody name/TN

Target

Year 1st approved

Indication(s)

nivolumab/Opdivo

PD-1

2014

mMel, NSCLC, RCC, HL, HNC, UC, CRC, HCC, SCLC, ESCC, mPM

pembrolizumab/Keytruda

PD-1

2014

mMel, NSCLC, HNC, HL, UC, GC, CC, HCC, MCC, RCC, SCLC, ESCC, EC, SCC

atezolizumab/Tecentriq

PD-L1

2016

BlC, NSCLC, BC, SCLC, HCC, mMel

avelumab/Bavencio

PD-L1

2017

MCC, UC, RCC

durvalumab/Imfinzi

PD-L1

2017

NSCLC, SCLC

cemiplimab/Libtayo

PD-1

2018

SCC, BCC, NSCLC

tislelizumab

PD-1

2019 (China only)

NSCLC (squamous & non- squamous), cHL, UC, HCC

dostarlimab/Jemperli

PD-1

2021

EC (mismatch repair deficient)

Abbreviations: BCC (basal cell carcinoma); BlC (bladder cancer); CC (cervical cancer); CRC (colorectal cancer); cHL (classical Hodgkin lymphoma); EC (endometrial cancer); ESCC (esophageal squamous cell carcinoma); GC (gastric cancer); HCC (hepatocellular carcinoma); HNC (head and neck cancer); MCC (Merkel cell carcinoma); mMel (metastatic melanoma); mPM (malignant pleural mesothelioma); NSCLC (non-small cell lung cancer); RCC (renal cell carcinoma); SCC (squamous cell carcinoma); SCLC (small cell lung cancer); UC (urothelial carcinoma)

The CTLA-4 checkpoint

CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4, CD152) is expressed by T cells, and is crucial for maintaining T cell homeostasis, by providing an inhibitory signal that balances against molecular signals that stimulate T cells. It binds to CD80/86 on antigen-presenting cells and prevents co-stimulation of both the T cells and antigen-presenting cells.

To date only one CTLA-4-targeted therapeutic antibody has been approved for immuno-oncology use. Ipilimumab (Yervoy) was first approved for clinical use in 2011. Yervoy is indicated for the treatment of metastatic melanoma, RCC, CRC, HCC, NSCLC and, malignant pleural mesothelioma.

The LAG-3 checkpoint

LAG-3 (lymphocyte activating 3, or CD223) is another inhibitory checkpoint protein that regulates T cell function, and restrains immune attack on normal cells. Relatlimab is a monoclonal antibody that binds to LAG-3 and prevents it from interacting with its ligands, MHC class II and fibrinogen-like protein1 (FGL1). Relatlimab is approved for clinical use in combination with the PD-1 inhibitor nivolumab (Opdualag), as a therapy for malignant melanoma.

Adverse effects

All of these checkpoint inhibitors are administered by injection/infusion and induce systemic T cell activation. They commonly cause widespread side-effects such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions that require monitoring and management. High dose corticosteroids may be required to suppress the hyperactivated immune system.

 

N.B.

It is instructive to note that the CTLA-4 immune checkpoint is also targeted as a therapeutic approach in autoinflammatory diseases, but in this field CTLA-4 mimetic peptides are used to promote the inhibitory activity of the CTLA-4/CD80/86 interaction on immune cell functions to down-modulate T cell-mediated inflammation and immune system hyperactivity. Two CTLA-4 mimetic fusion proteins are approved for clinical use

Drug INN/TN

Year 1st approved

Indication(s)

abatacept/Orencia

2005

severe rheumatoid arthritis, juvenile rheumatoid arthritis and active psoriatic arthritis

belatacept/Nulojix

2011

prophylaxis of organ rejection after kidney transplant

 

This web resource provides information about immunotherapeutics, including access to their protein sequences and approval or development status. It includes antibodies, nanobodies and Ig-based fusion proteins (-fusps). Thera-SAbDab is updated regularly and is a good resource for those who seek in-depth information about these biologic entities.

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Immune Checkpoint inhibitors

Immune checkpoint (IC) proteins are regulators of inhibitory signalling pathways that are essential for homeostasis of the T cell-mediated immune response. Immune checkpoint inhibitors are (generally) monoclonal antibodies that are used as a type of cancer immunotherapy and that act to re-establish immune detection and T cell-directed attack on tumours. Whilst these agents can be highly effective, they do not work for every patient, with certain cancers being inherently resistant to this pharmacological approach. Therapy-induced resistance to these agents can develop.  Barrueto et al. (2020) provide an extensive review of the immune checkpoints, and the molecular mechanisms that can lead to resistance (PMID: 32114384).

The image below is a simplified diagram of the ICs that are targeted by currently approved monoclonal antibodies. It focuses on the communications between tumour cells and T cells, but does not include T cell receptors and other accessory proteins that may be components of the functional checkpoint complexes.

Adapted from “Cell Immunotherapy (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

The PD-1/PD-L1 checkpoint

PD-1 (programmed cell death 1, a.k.a. PDCD1 or CD279) is a transmembrane protein on immune cells that interacts with the membrane-bound ligand PD-L1 (PD-1 ligand 1, or CD274). The PD-1/PD-L1 interaction is a key inhibitory checkpoint in T cell activation. Some cancers aberrantly express PD-L1 which allows them to evade immune surveillance and disrupts T cell-mediated anti-tumour immunity.

Therapeutic monoclonal antibodies have been developed to target either PD-1 or PD-L1 to correct the immunosuppressive effect of PD-1/PD-L1 pathway signalling within the tumour microenvironment, and to re-initiate T cell killing of tumour cells.

Approved antibodies (May 2022)

Antibody name/TN

Target

Year 1st approved

Indication(s)

nivolumab/Opdivo

PD-1

2014

mMel, NSCLC, RCC, HL, HNC, UC, CRC, HCC, SCLC, ESCC, mPM

pembrolizumab/Keytruda

PD-1

2014

mMel, NSCLC, HNC, HL, UC, GC, CC, HCC, MCC, RCC, SCLC, ESCC, EC, SCC

atezolizumab/Tecentriq

PD-L1

2016

BlC, NSCLC, BC, SCLC, HCC, mMel

avelumab/Bavencio

PD-L1

2017

MCC, UC, RCC

durvalumab/Imfinzi

PD-L1

2017

NSCLC, SCLC

cemiplimab/Libtayo

PD-1

2018

SCC, BCC, NSCLC

tislelizumab

PD-1

2019 (China only)

NSCLC (squamous & non- squamous), cHL, UC, HCC

dostarlimab/Jemperli

PD-1

2021

EC (mismatch repair deficient)

Abbreviations: BCC (basal cell carcinoma); BlC (bladder cancer); CC (cervical cancer); CRC (colorectal cancer); cHL (classical Hodgkin lymphoma); EC (endometrial cancer); ESCC (esophageal squamous cell carcinoma); GC (gastric cancer); HCC (hepatocellular carcinoma); HNC (head and neck cancer); MCC (Merkel cell carcinoma); mMel (metastatic melanoma); mPM (malignant pleural mesothelioma); NSCLC (non-small cell lung cancer); RCC (renal cell carcinoma); SCC (squamous cell carcinoma); SCLC (small cell lung cancer); UC (urothelial carcinoma)

The CTLA-4 checkpoint

CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4, CD152) is expressed by T cells, and is crucial for maintaining T cell homeostasis, by providing an inhibitory signal that balances against molecular signals that stimulate T cells. It binds to CD80/86 on antigen-presenting cells and prevents co-stimulation of both the T cells and antigen-presenting cells.

To date only one CTLA-4-targeted therapeutic antibody has been approved for immuno-oncology use. Ipilimumab (Yervoy) was first approved for clinical use in 2011. Yervoy is indicated for the treatment of metastatic melanoma, RCC, CRC, HCC, NSCLC and, malignant pleural mesothelioma.

The LAG-3 checkpoint

LAG-3 (lymphocyte activating 3, or CD223) is another inhibitory checkpoint protein that regulates T cell function, and restrains immune attack on normal cells. Relatlimab is a monoclonal antibody that binds to LAG-3 and prevents it from interacting with its ligands, MHC class II and fibrinogen-like protein1 (FGL1). Relatlimab is approved for clinical use in combination with the PD-1 inhibitor nivolumab (Opdualag), as a therapy for malignant melanoma.

Adverse effects

All of these checkpoint inhibitors are administered by injection/infusion and induce systemic T cell activation. They commonly cause widespread side-effects such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions that require monitoring and management. High dose corticosteroids may be required to suppress the hyperactivated immune system.

 

N.B.

It is instructive to note that the CTLA-4 immune checkpoint is also targeted as a therapeutic approach in autoinflammatory diseases, but in this field CTLA-4 mimetic peptides are used to promote the inhibitory activity of the CTLA-4/CD80/86 interaction on immune cell functions to down-modulate T cell-mediated inflammation and immune system hyperactivity. Two CTLA-4 mimetic fusion proteins are approved for clinical use

Drug INN/TN

Year 1st approved

Indication(s)

abatacept/Orencia

2005

severe rheumatoid arthritis, juvenile rheumatoid arthritis and active psoriatic arthritis

belatacept/Nulojix

2011

prophylaxis of organ rejection after kidney transplant

 

This NIH National Cancer Institute webpage provides more information about how immune checkpoint inhibitors (ICIs) work against cancer, and which types of cancer are currently treated with ICIs. There are links to further resources that cover additional aspects of cancer immunotherapy.

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Introduction to antineoplastics

Cancer chemotherapy has changed dramatically and advances in our understanding of cancer biology is facilitating development of drugs that produce cures.

Chemotherapy may be indicated as a primary treatment or as adjuvant or neoadjuvant therapy. The former is used when there are no other effective treatment approaches. Adjuvant therapy is used to eradicate micrometastatic disease following localized treatments such as surgery or radiation or both. Neoadjuvant chemotherapy is used to make other treatment modalities more effective by reducing tumor burden and to destroy micrometastases.

Despite the high cure rates of previously lethal cancers, the use of these drugs is associated with significant harmful effects. Thus, a thorough understanding of the pharmacology of the antineoplastics is important for their safe and effective use in clinical practice.

The compounds used in cancer chemotherapy are varied in structure and mechanism of action, including alkylating agents; antimetabolite analogs; natural products; hormones and hormone antagonists; and a variety of agents directed at specific molecular targets.

  • Alkylating drugs and platinum compounds: These drugs are the classical cytotoxic drugs which chemically bind with macromolecules such as DNA and disrupt cell dynamics, growth and differentiation.
  • Anthracyclines: These drugs disrupt DNA replication and transcription by DNA intercalation, a type of physical binding. Ultimately, they shift the balance in favor of cancer cell apoptosis.
  • Antimetabolites: These drugs disrupt the metabolism inside the cells by inhibiting folate metabolism and/or DNA synthesis.
  • Topoisomerase inhibitors: inhibit the release of supercoils during DNA replication and transcription and thus disrupt DNA dynamics.
  • Antimitotic Drugs (Vinca alkaloids and Taxanes): Inhibit the dynamic instability of microtubules and thus arrests the cell cycle in mitosis.
  • Protein kinase inhibitors and Antibodies: These are relatively new group of drugs which target specific growth receptors and thus help control cell growth and differentiation.

The biological targets of anticancer therapy are present throughout the cell, from cell membrane to nucleus. The cell cycle specificity is an important attribute and it determines the selection of drug regimen, among other factors. Likewise, ability to eradicate cancer cells can be judged with log-kill hypothesis.

Dr Nasir Afsar

This 42-minute video introduces the concept of chemotherapy for cancer. In addition to a short description of the log kill hypothesis, the mechanisms of action of the main classes of antineoplastic drugs are described. These include the cytotoxic drugs (e.g. alkylating agents), hormones, and immunoglobulins and tyrosine kinase inhibitors. The video concludes with a general overview of the general principles of chemotherapy and adverse effects. This video would be appropriate for learners as they begin their study of antineoplastic drugs. Presentation created and contributed by Dr Nasir Afsad, Alfaisal University College of Medicine, Riyadh, Saudi Arabia.

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