cancer drugs and vaccines

What is the basic principle of curative cancer surgery?

Surgery involves physically removing:

• the cancerous tissue, and

• some surrounding healthy tissue.

For what type of cancer is surgery most effective?

solid tumours that remain contained within one area

What are the major limitations of curative surgery?

• Potential damage to organs

• Surgery may remove some but not all cancer cells - risk of reoccurrence

• May be impossible when the tumour is close to delicate tissues or vital structures

• Poor effectiveness for highly metastatic tumours

Why is surgery poorly suited to highly metastatic cancer?

Surgery is a local treatment.

Once malignant cells have spread to multiple distant sites, removing one primary tumour cannot necessarily eliminate all metastatic tumour deposits.

Why can cancer recur after apparently successful surgery?

Surgery may fail to remove every malignant cell. Residual cells may survive, proliferate and eventually produce recurrent disease.

What forms of radiation are used for radiotherapy?

Photons

• gamma rays;

• X-rays.

Particle beams

• protons;

• neutrons;

• electrons.

What is the mechanism of action of radiotherapy?

Radiation damages cellular DNA, impairing the cell's ability to reproduce, leading to cancer-cell death

Why can radiotherapy preferentially eliminate cancer cells despite also damaging healthy cells?

cancer cells have a more impaired ability to repair the damage, making them more likely to undergo cell death

What limits the dose of radiotherapy that can be administered?

All tissues have a tolerance level or maximum dose, above which irreparable damage may occur

What are the major limitations of radiotherapy?

• Damage to surrounding healthy tissue

• Tumour cells not visible on imaging may be missed

• Some tumours show limited responsiveness to radiation

What is chemotherapy?

Chemotherapy is the treatment of cancer using cytotoxic drugs.

What systemic routes of chemotherapy administration are identified in the lecture?

• Intravenous — IV

• Intramuscular — IM

• Subcutaneous — SC

• Oral

What are the four major intents of chemotherapy?

Curative
→ aggressive treatment intended to eradicate cancer.

Neoadjuvant
→ given before surgery to decrease tumour size.

Adjuvant
→ given after surgery, or with radiotherapy, to remove remaining cancer cells.

Palliative
→ used to prolong life and/or reduce symptoms rather than cure disease.

What is the fundamental aim of cytotoxic chemotherapy?

Chemotherapy aims to produce a lethal cytotoxic event in cancer cells, thereby arresting tumour progression

Why do conventional chemotherapeutic drugs cause substantial toxicity

Most chemotherapeutic drugs do not specifically recognise neoplastic cells.

Instead, they also affect normal proliferating cells

What is the log-kill hypothesis?

The log-kill hypothesis states that the cytotoxic actions of anticancer drugs follow first-order kinetics.

A given dose kills a constant fraction/proportion of tumour cells, rather than a constant absolute number

Do chemotherapeutic drugs kill a fixed number or a fixed percentage of tumour cells

A fixed percentage

How does the log-kill hypothesis help explain the need for repeated chemotherapy cycles?

Because each treatment destroys a fraction rather than every tumour cell, surviving cells remain after each treatment. Repeated treatment can therefore progressively reduce the malignant-cell population.

When are cell-cycle-specific drugs most effective?

CCS drugs are particularly effective when a large proportion of tumour cells are proliferating

What mechanisms of chemotherapy resistance are mentioned

• Increased cell-membrane efflux-pump activity

• Decreased uptake of the chemotherapeutic drug

Summarise the main limitations of chemotherapy from the lecture

• Tumour-cell kinetics can reduce drug susceptibility

• Many tumour cells may not actively be dividing

• Cancer cells can develop drug resistance

• Decreased drug uptake can reduce effectiveness

• Cytotoxicity to normal proliferating cells causes side effects

Why are cancer cells suitable targets for monoclonal antibodies?

Cancer cells can express a variety of cell-surface antigens that provide attractive molecular targets for monoclonal antibody therapy

What is the basic principle of monoclonal antibody cancer therapy?

Cancer cell expresses particular antigen
→ antibody selectively recognises that antigen
→ antibody binds the tumour-associated target
→ cancer cells can then be inhibited or destroyed.

What is HAMA

Human anti-mouse antibody response.

Murine monoclonal antibodies can be recognised as foreign by the human immune system, leading to an immune response against the therapeutic antibody

What is a chimeric monoclonal antibody?

A chimeric monoclonal antibody combines:

• Human constant regions
  with

• Intact rodent variable regions

Affinity and specificity are retained, although anti-chimeric immune responses can still occur.

What is a humanised monoclonal antibody?

Humanised antibodies contain only the rodent complementarity-determining regions (CDRs) grafted onto a human variable-region framework

What is a “naked” monoclonal antibody?

“Naked” means the antibody is not fused to a toxin.

Naked antibodies can kill target cells via:

• Antibody-dependent cellular cytotoxicity (ADCC)

• Complement-dependent cytotoxicity (CDC)

• Direct induction of apoptosis

What mechanisms can naked monoclonal antibodies use to kill cancer cells?

ADCC
→ antibody-coated cells become targets for immune effector mechanisms.

CDC
→ antibody binding promotes complement-mediated destruction.

Direct apoptosis
→ antibody binding can directly trigger tumour-cell death.

How can monoclonal antibodies be modified to act as delivery systems?

They can be conjugated to an active agent such as:

• Toxin

• Radioisotope

• Cytokine

• Other active conjugate

What is a bispecific antibody?

bispecific antibodies as antibodies capable of binding both:

• A target antigen
  and

• A conjugate or effector cell

through their Fab regions.

What is rituximab and what does it target?

Rituximab is a chimeric monoclonal antibody targeting the CD20 B-cell antigen.

How does rituximab produce its therapeutic effect?

rituximab effectively flags B cells for destruction by the patient's own immune system.

This eliminates B cells, including malignant B cells, after which healthy B cells can subsequently be regenerated from lymphoid stem cells

Why is CD20 an attractive target in B-cell cancers?

it is expressed on a high proportion of B-cell neoplasms, allowing rituximab to target cells belonging to the malignant B-cell population.

What is gemtuzumab ozogamicin?

Gemtuzumab ozogamicin (Mylotarg) is a monoclonal antibody conjugated to the cytotoxic agent calicheamicin

What cancer is gemtuzumab ozogamicin used to treat according to the lecture?

Acute myelogenous leukaemia (AML)

What does gemtuzumab ozogamicin target?

It targets the CD33 receptor, which is found on most leukaemic blast cells but not on normal haematopoietic stem cells.

What principle of targeted therapy is illustrated by gemtuzumab ozogamicin?

Antibody identifies tumour-associated antigen
→ antibody carries cytotoxic agent to target cell
→ increased targeting of the malignant-cell population.

What is trastuzumab and what does it target?

Trastuzumab (Herceptin) is an anticancer monoclonal antibody directed against the HER2/neu (erbB2) receptor

Why does HER2 expression determine susceptibility to trastuzumab?

only cells overexpressing the HER2 receptor are susceptible

major limitations of monoclonal antibody cancer therapy?

Only a minority of patients may respond, with many developing refractory disease.

Antibodies can have poor penetration and heterogeneous distribution within solid tumours.

Efficacy depends on tumour cells actually expressing the target molecule.

Both intrinsic and acquired resistance can occur.

How can tumours acquire resistance to monoclonal antibody therapy?

Mutations can occur in:

• the antibody target itself

or

• downstream signalling molecules.

These alterations may activate alternative growth or survival pathways, allowing the cancer cell to continue functioning despite antibody treatment.

Where do T cells originate and mature?

T-cell progenitors are formed in the bone marrow and migrate to the thymus, where they mature into T cells

What receptors are expressed by conventional T cells?

T cells express a T-cell receptor (TCR) and either a CD4 or CD8 receptor

What is a chimeric antigen receptor (CAR)

an engineered receptor that gives a T cell the ability to target a specific antigen, it combines:

• antigen-binding activity

• T-cell activating functions

within a single receptor.

What are the two fundamental components of a CAR

• an extracellular antigen-recognition domain

• an intracellular signalling domain that activates the T cell.

What is the therapeutic concept behind CAR-T therapy?

A patient's T cells are genetically modified so that they express a receptor capable of recognising a selected tumour-associated antigen.

The engineered cells can then be returned to the patient and used as targeted cytotoxic immune cells.

What is the first stage of producing CAR-T cells?

leukapheresis

T cells are isolated and collected from the patient's peripheral blood

What happens during T-cell activation in CAR-T manufacture?

The collected T cells are activated, and transformed into cytotoxic T cells

How is the CAR introduced into the patient's T cells?

During the genetic-modification/transfection stage, a gene is inserted using a virus, causing the T cell to express the CAR

Why are engineered CAR-T cells expanded in culture?

The cells are maintained in culture so that they expand and proliferate, creating sufficient engineered cells for therapeutic administration

Outline the CAR-T therapy process step by step.

→ leukapheresis

→ T-cell activation

→ genetic modification/transfection: CAR gene introduced

→ T cells express the CAR

→ cell expansion

→ purification/cryopreservation where required

→ infusion into patient

→ engineered T cells recognise the target antigen

What are the key limitations of CAR-T therapy emphasised in this lecture?

• difficulty of scaling therapy to larger patient populations and broader indications

• difficulty of scaling therapy to larger patient populations and broader indications

• it is a complex manufacturing process

• Generating consistently high-quality viral vector

What samples are required to design the personalised cancer vaccine described in the lecture?

• patient tumour biopsies

• healthy tissue

are analysed, having both allows tumour DNA to be compared against the patient's normal DNA

What technique is used to analyse tumour and healthy tissue when developing the personalised cancer vaccine

next-generation sequencing (NGS)

Why are tumour and normal DNA sequences compared when designing a cancer vaccine?

The comparison allows researchers to identify tumour-specific differences in protein-coding genes.

These differences may generate mutant proteins or peptides that distinguish the cancer cells from normal cells

What is a neoepitope

a vaccine target derived from a tumour-specific mutation

Why is computational analysis required during personalised cancer-vaccine development?

Sequencing may identify multiple tumour-specific mutations.

A computational pipeline evaluates the corresponding mutant peptide regions for HLA binding, helping select mutations suitable for incorporation into the personalised vaccine

Outline a successful cancer-vaccination strategy step by step

• Obtain samples: Collect a tumour biopsy and healthy tissue from the patient.

• Sequence both samples: Perform next-generation sequencing of tumour and normal DNA.

• Compare tumour vs normal DNA: Identify tumour-specific differences in protein-coding genes.

• Identify mutant peptides: Determine the peptide sequences generated by tumour-specific mutations.

• Analyse HLA binding: Use a computational pipeline to examine mutant peptide regions for binding to the patient's HLA.

• Select suitable mutations: Identify multiple tumour-specific mutations that can be incorporated into a personalised vaccine.

• Manufacture vaccine

• Administration