Cell therapeutics Flashcards
What is adoptive cell therapy
Adoptive Cell Therapies: using a patient’s immune cells to fight Off disease
What is a DC is and its role in immunity?
- Professional APC - antigen processing
- Bridges adaptive and innate immunity
- Most potent APC: In cancer, they present tumor antigens
- T cell responses are initiated by activated DCs
What is DC in vivo activation, in vivo expansion, and blocking of inhibitory signals
in vivo activation: Provide exogenous activation signals (attempt to reverse supression)
in vivo expansion: DCs are not high in number in the TME. Hypothesis: increasing the number of intratumoral cDC could increase the cumultative function of the population
blocking of inhibitory signals: A suppression microenvironment is a key regulator of cDC function. Hypothesis: BLocking inhibitory pathways that reduce cDC functionality may enhance the activation state of tumor cDC
What is a γδ Τ cell is and its role in healthy individuals compared to cancer patients
A subset of T cells, bearing a γδ heterodimer as a T cell receptor (TCR)
Healthy individuals:
γδT cells are naturally biased towards a cytotoxic phenotype,
producing antitumor cytokines IFNγ-, TNF.
Newborns harbor a population of circulating IFNγ- and TNF-positive
γδT cells.
Diversity generated by microbial encounter, leading to functional
diversity.
Cancer patients:
Tumour encounter through γδT cells can result in anergy or the
deletion of γδT cells.
IL-17 production by γδT cells enhances tumour progression.
Increase the expression of myeloid derived suppressor cells (MDSCs)
in the TME
Describe different ways that γδ Τ cells can be exploited for therapies. Focus mainly on DOT cells
Goal: To induce de novo expression of natural cytotoxic receptors, particularly NKP30 and nkP44, while also upregulating the expression of NKG2D and DNAAM1
–> enhances an NK cell response
Method: This is achieved by a Vδ1-enriched (>60%) γδT cell product for adoptive transfer, produced in a period of over 3 weeks under stimulation with TCR agonists and cytokines.
What is a NK cell and its biological role
-Innate immune cell
-2 - 18% of human peripheral blood lymphocytes
-Widely found in the spleen and lymph nodes
-Able to distinguish between heathly, stressed and transformed cells
-Activated;
a) via receptors: Able to lyse cells without prior stimulation
b) Via antibody-dependent cellular cytotoxicity
-Primed in response to various cytokines (e.g. IL-2, IL-15)
-Release cytotoxic granules (e.g. perforin, granzyme)
Describe the three main treatment modalities targeting NKs (cytokine supplements, monoclonal antibodies, adoptive cell therapy)
Cytokine supplements:
IL-15: expands NK cells
IL-21: important in maturation
IL-12: Critical for NK memory cell formation
IL-2: enhance their cytolytic activity
Can be combined with other therapies to give synergistic effect.
Monoclonal antibodies:
Blocking KIRs would allow a more efficient NK cell cytotoxicity
Epidermal growth factor receptor inhibitor treatment: NK cells are more enriched in the TME
MICA antibodies: prevention of NK cell recognition –> prevention of inhibition in TME
Adoptive cell therapy:
adoptive transfer:
Transfer of NK cell along with CD34+ HSCs is promising
Antibody engineering:
BiKES and TRiKES
BiKE connects a single-
chain variable fragment (scFv) to the anti-CD16 recogni-
tion site with the scFv of a tumor specific antigen, such
as CD19/CD20 for non-Hodgkin lymphomas
TriKE consists of a BiKE and cyto-
kine IL-15, which boost NK cell function and survival
Genitic modification:
Culture in vitro and differentiate in CAR-NK in vivo
Or deleting surface molecules (e.g. CD38) which enhances cytotoxic ability
What is the difference of engineered vs non-engineered T cell therapies?
Non-engineered immune cell therapies typically include apheresis, turmor resection or banked donor T cells which are subjected to Treg isolation and expansion; T cells isolation and expansion; Expansion, respectively. These will in turn yield Tregs, TILs and Viral-specific CTLs
Engineered immune cell therapies are generated by
first apheresing or drawing blood from the patient, isolating T cells, and using viral or non-
viral approaches to insert a transgene encoding a synthetic receptor. These can yield engineered TCRs, CAR-T, CAAR-T, CAR-Treg or CAR-NK
Describe the three main non-engineered treatment modalities targeting T cells (TILs, viral-specific CTLs, Treg cells)
TILs: tumor-infiltrating lymphocytes
Ex vivo expansion and re-infused in patients with IL-2
Viral-specific CTLs: cytotoxic t lymphocytes
Infusion of donor leukocytes pre sensitized to EBV
ex/in vivo expansion and transfusion of autologous or allogeneic Tregs Therapeutic strategy!
Reflect on the advantages of cellular therapeutics over another type of biopharmaceutical
Cellular therapies are precise and lower the risk of drug resistance, although ADAs are a risk. Cell therapeutics are a first gen-technology and expensive and often personalized
Drawback of DC in vivo activation/expansion?
Single-agent administration in patients is not efficacious
DOT therapy drawback?
Drawback: potential downraguation of these naturally expressed receptors once the cells are infused into a patient
What is the NK cell therapy goal?
To enhance NK cell function and cytotoxicity
What is a drawback with TILs?
Not enough to remove tumor on its own
What is a drawback with viral-specific CTLs?
Patients can be immunized against donor cell products. Alternative methods use the patients’s own virus-specific immune cells or modify T cells with virus-specific properties
