Immunotherapy modalities Flashcards
What are the 5 pillars of cancer care?
Surgery (ancient times-present), radiotherapy (1890s-present), cytotoxic chemotherapy(1940s-present), molecularly targeted therapy (1990s-present) and immunotherapy (1990s-present)
What is the difference between passive and active immunotherapy?
The difference is based on their ability to (re-)activate the host immune system against malignant cells.
Passive immunotherapies are endowed with intrinsic antineoplastic activity (e.g. Tumour-targeting monoclonal antibodies (mAbs) and adoptively transferred T cells)
Active immunotherapies exert anticancer effects only upon the engagement of the host immune system (e.g. Anticancer vaccines and checkpoint inhibitors)
What is an alternative way to divide types of immunotherapies? (the other way is passive and active immunotherapy)
Antigen-specific vs. non-antigen-specific/broad. • Antigen-specific: o Vaccine o CAR-T cell • Broad (non-antigen specific): o Immunostimulatory cytokines o Checkpoint blockers
What can tumour-targeting antibodies do?
Specifically alter the signalling functions of receptors expressed on the surface of malignant cells. E.g., Anti-EGFR
Bind to, and hence neutralize, trophic signals produced by malignant cells or by stromal components of neoplastic lesions. E.g., Anti-VEGF
Selectively recognize cancer cells based on the expression of a “tumour-associated antigen” (TAA), i.e., an antigen specifically (or at least predominantly) expressed by transformed cells but not (or at least less so) by their non-malignant counterparts. E.g. Anti-CD20 in CLL.
What are the 5 functional variants of mAbs?
•Naked mAbs that inhibit signalling pathways required for the survival or progression of neoplastic cells, but not of their non-malignant counterparts:
o EGFR-specific mAb cetuximab
•Naked mAbs that activate potentially lethal receptors expressed on the surface of malignant cells, but not of their non-transformed counterparts:
o TRAILR2-specific mAb tigatuzumab
•Immune conjugates, i.e., TAA-specific mAbs coupled to toxins or radionuclides:
o Gemtuzumab ozogamicin, an anti-CD33 calicheamicin conjugate
•Naked TAA-specific mAbs that opsonize cancer cells and activate antibody- dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity:
o CD20-specific mAb rituximab
•Bispecific T-cell engagers (BiTEs), i.e., chimeric proteins consisting of two single-chain variable fragments from distinct mAbs, one targeting a TAA and one specific for a T-cell surface antigen:
o Blinatumomab, a CD19- and CD3 BiTE
What is adoptive cell transfer?
A particular variant of cell-based anticancer immunotherapy that generally involves:
(1) the collection of circulating or tumour-infiltrating lymphocytes;
(2) their selection/ modification/expansion/activation ex vivo;
and (3) their (re-)administration to patients, most often after lymphodepleting pre-conditioning and in combination with immunostimulatory agents
What are the differences between HSCT (hematopoietic stem cell transplantation) and Adoptive cell transfer (ACT)?
ACT involves the (re-)introduction of a cell population enriched in potentially tumour-reactive immune effectors.
HSCT is employed as a means to reconstitute a healthy, allogeneic (and hence potentially tumour-reactive) immune system in patients with haematological malignancies previously subjected to myelo- and lympho-ablating treatments (which aim at eradicating the majority of neoplastic cells)
What are the differences between a DC infusion and Adoptive cell transfer?
Re-infused DCs are not endowed with intrinsic anticancer activity, but act as anticancer vaccines to elicit a tumour-targeting immune response.
DCs are not administered in the context of lympho/myeloablating haemo(radio)therapy
What are oncolytic viruses?
Non-pathogenic viral strains that specifically infect cancer cells, triggering cell death.
What are oncotrophic viruses and what is the difference with oncolytic viruses?
Oncotrophic viruses exhibit a preferential tropism for malignant cells but have no (or very limited) cytotoxic activity. E.g. baculovirus-mediated gene delivery.
Oncolytic viruses DO have cytotoxic activity
What is the mechanism of oncolytic viruses?
Cytopathic effect, i.e., the lethal overload of cellular metabolism resulting from a productive viral infection
Endogenous or exogenous gene products that are potentially lethal for the host cell, irrespective of their capacity to massively replicate and cause a cytopathic effect
They promote the release of TAAs in an immunostimulatory context
What do you have to watch out for with oncolytic viruses?
Anti-viral immune responses: Virus capture, neutralizing antibodies, complement, etc
What are peptide and DNA based cancer vaccines and what is the rationale behind them?
Full-length recombinant TAAs or peptides thereof are administered to cancer patients, most often via the intramuscular, subcutaneous or intradermal route, together with one or more immunostimulatory agents commonly known as adjuvants (which potently promote DC maturation)
The rationale behind this approach is that resident DCs (or other APCs) acquire the ability to present the TAA-derived epitopes while maturing, hence priming a robust TAA-specific immune response
What is the use of immunostimulatory cytokines in immunotherapy?
Cytokines regulate (via autocrine, paracrine or endocrine circuits) virtually all biological functions. The administration of most immunostimulatory cytokines to cancer patients as standalone therapeutic interventions, however, is generally associated with little, if any, clinical activity. Thus, immunostimulatory cytokines are generally employed as adjuvants for other anticancer (immuno)therapeutics, either as recombinant molecules or encoded within expression vectors
Notable exceptions include IFN-α2b (Intron A), and IL-2 (aldesleukin or Proleukin), which mediate single agent therapeutic activity in patients affected by melanoma
How do immunomodulatory mAbs operate?
Immunomodulatory mAbs operate by interacting with (hence altering the function of) soluble or cellular components of the immune system:
(1) the inhibition of immunosuppressive receptors expressed by activated T lymphocytes, such as CTLA4 and PD-1, or NK cells, like various members of the killer cell immunoglobulin-like receptor (KIR) family;
(2) the inhibition of the principal ligands of these receptors, such as PD-L1;
(3) the activation of co-stimulatory receptors expressed on the surface of immune effector cells such as TNFRSF4 (OX40), TNFRSF9 (4-1BB), and TNFRSF18 (GITR);
(4) the neutralization of immunosuppressive factors released in the tumour microenvironment, such as transforming growth factor β1 (TGFβ1).
