Lecture 36 - Cell based Therapies

Question 1

What are regulatory T cells (Tregs)

Answer 1

Specialized TH cell subpopulation (CD4+, CD25+, FoxP3+) that
inhibit adaptive and innate immune responses.

Human Tregs are characterized with Forkhead box P3 (Foxp3) transcription factor protein along with low and high expression of CD45RA marker.

Question 2

What does Treg-mediated immunosuppression involve

Answer 2

CTLA4-mediated downregulation of APC activity via upregulation of indolamine 2,3 dioxygenase (IDO), a potent immunosuppressive enzyme

IL-2 consumption due to increased CD25 expression

immunosuppressive cytokine and metabolite production. IL-10, TGF-β, and adenosine, granzyme and perforin

Question 3

What is a summary of Treg effects

Answer 3

Secretion of anti inflammatory cytokines that supresses Th1, Th17, and APC activity

Inhibition of DC function - disrupts maturation and inhibiting Teff activation

Secretion of granzymes and perforin - apoptoses Teff cells (cytolysis)

Starve Teff cells of IL-2 signalling

Produce adenosine, inhibits Teff cell response

Question 4

How do Tregs effect Autoreactive B cells

Answer 4

inhibit autoreactive B cells so decreasing autoantibodies. mediated by PD-1 (B cell)/ PDL-1 (Tregs) interactions + perforin/ granzyme mechanisms

Question 5

How do Tregs effect Neutrophils

Answer 5

Suppress them

Induce M2 (antiinflammatory) macrophage phenotype

Question 6

Tregs can suppress NK cell activity, resulting in tumor progression

Answer 6

yh

Question 7

How are Tregs isolated for trials

Answer 7

either peripheral blood or umbilical cord blood.

(Tested in models of IL-10-/- knock out murine model for colitis - examine efficacy of Treg cell producing IL-10 to reverse the pathological condition

First clinical trial in humans with single infusion of PBMC-derived freshly isolated Tregs (106–109) to a patient with active Crohn’s disease was safely initiated during 2012)

Question 8

How do Treg numbers change in autoimmune conditions

Answer 8

decreased in autoimmune patients

Adaptive transfer of Tregs in mice model using collagen-induced arthritis (CIA) showed inhibitory effects on arthritis dampening of not only T and B cells but decrease in osteoclast-mediated bone destruction.

Indication a-TNF therapies can enhance Treg activity

Question 9

What injections may reestablish treg function

Answer 9

infiltration of Tregs into skin tissue in patients but cells inactive due to high IL-17 and lack of IL-2
rIL-2 injections re-established T reg function

Question 10

What are mesenchymal stem cells

Answer 10

Adult stem cells- They exist in nearly all tissues and play a significant role in tissue repair and regeneration

Question 11

What type of potency are mesenchymal stem cells

Answer 11

Multipotent stem cells characterized by self-renewal, production of clonal cell populations, and multilineage differentiation.

Question 12

What properties o Mesenchymal stem cells possess

Answer 12

They possess wide immunoregulatory properties via interaction with immune cells in both innate and adaptive immune systems, leading to immunosuppression of various effector functions.

Increasing studies have attempted to apply MSCs for the treatment of several autoimmune disorders

Question 13

What are the immunomodulatory effects of MSCs

Answer 13

Secrete numerous bioactive molecules, (often in extracellular vesicles) which exert autocrine/paracrine effects that modulate immune cells.

Accelerate generation of M2 macrophages and regulatory T cells,

Suppress maturation of monocytes and proliferation of T cells and B cells

Mediated largely by PGE2 , TGFb and IDO

Question 14

What does the immunomodulatory effects of MSC require

Answer 14

requires prestimulation by inflammatory cytokines, such as TNF-a and IL- 1

Question 15

What are some MSC therapies

Answer 15

MSCs have the privilege of exerting immune-mediated actions without a requirement for host-recipient matching, attributed to low expression of HLA class I antigen and HLA class II antigen on MSC surfaces(so better than HSCs)

Being investigated for a range of autoimmune disorders such as multiple sclerosis, Crohn’s disease, graft versus host disease (GVHD), and systemic lupus erythematosus (SLE)

The first successful MSC therapy comprised infusion of MSCs obtained from bone marrow into an acute GVHD-grade patients with cyclosporine- and steroid-resistant features

Question 16

What is MS

Answer 16

Multiple sclerosis (MS) is a CD4 T cell-modulated autoimmune disease targeting myelin-based protein (MBP) and currently, one of the most prevalent autoimmune diseases in the central nervous system (CNS). (2.3 million people)

Question 17

How can MSCs exert therapeutic effects in MS

Answer 17

Currently 31 clinical trials of MS researching the MSC effectiveness and adverse effects for treatment MS patients all over the world, proof of concept of iv administration of MSCs from autologous bone marrow for patients with MS

However, currently no significant positive achievements reached and further investigations are needed before they can be widely applied to clinical treatment.

Question 18

What are the clinical potentials of MSC treatment

Answer 18

Currently, MSC treatment has already entered clinical trials for the treatment of organ transplantations, tissue regeneration, and autoimmune diseases.
Deemed safe, however, long term effects of treatment are not yet assessed
Possible complications of MSC therapy are

Question 19

What are the risks of using MSCs

Answer 19

Potential reduction in immune response to pathogens

Potential induction of tumors by changing the action of cancer cells and accelerating tumor cell growth.

In addition, allogeneic MSCs derived from donors may accelerate infectious risk.

Further information required on durability of response, delivery mechanism and dose, safety control, as well as optimized standards for MSC derivation and amplification

Question 20

What are some other cell based therapies besides MSC

Answer 20

Tumour infiltrating lymphocyte (TIL) therapy

T cell receptor (TCR) or Chimeric antigen receptor (CAR) T cell therapy

Innate immune cell based therapy

Question 21

What is the first cancer TIL therapy to get FDA approval

Answer 21

Lifileucel (Amtagvi), the first treatment for cancer that uses
tumor-infiltrating lymphocytes, or TILs.

Approved formelanoma (skin cancer).

T cells are collected from the patient’s tumor.

70 participants took part in first trials-,
nearly one-third had at least some reduction in the size of their tumors (a tumor response), with tumors disappearing completely in several participants.

Moreover, about 40% of those whose cancer responded to lifileucel still had no progression of their cancer a year after receiving the one-time infusion treatment.