T cell therapy for cancer

• T cell therapies for cancer - immunotherapy

  Therapies that use T cells to treat cancer

  
• Revised


  Not started
• Role of T cells in health:
• Development of T lymphocytes


  Common lymphoid progenitor in the bone marrow > thymus > differentiated into CD4/8 T cells which then undergo further differentiation

  
• Conditions which causes the absence of T cells

  • SCID, HIV
• CD8 cells


  • Responsible for killing cells infected with virus - induction of apoptosis destroys all DNA material in the cell > prevents viral material from escaping and causing further infection

  Protect against IC pathogens
• Effector function of CD8 cells


  Cytotoxic, Secrete cytokines like IFNy
• Took cancer specific T cell 78 hrs to kill the cancer cells
• Current therapies for cancer

  • Surgery

  Chemotherapy

  Radiation

  Hormone/GF blocking

  Bone marrow transplantation
• Current therapies have limited effectiveness against advanced/metastatic/recurrent disease with side effects that can severely affect quality of life
• Ideal therapy


  Should be specific for cancer and non-toxic to normal cells

  
• Using CD8 T cells for therapy of cancer

  Adoptive cell therapy:

  Lymphodepletion by CHE is needed before treatment

  Higher success rate than cancer vaccines

  T cells from patient are collected and expanded. Cancer specific cells are chosen and put back into the patient

  
• Isolation of specific T cells from blood or other tissue


  Patients/healthy donors

  Proof that T cells can kill cancer cells in vitro

  Growth of specific T cells to large numbers under sterile conditions

  Multiple transfusions required

  Prevent infection/toxicity

  Good manufacturing practice GMP

  Location of manufacturing plants

  
• Targets for T cells - tumour specific Ags


  • Viral proteins (15% of all cancers are caused by viruses > normal cells will not have virus > targeted therapy)

  NeoAgs - cancer are due to genetic abnormalities > different expression of certain proteins that are not expressed in normal cells but present in cancer cells. MRNA cancer vaccines are based on neoAgs

  
• T cells from an unrelated, HLA matched donor can cause destruction of the brain tumour
• Melanoma skin cancer


  UK incidence 16000 cases with 2000 deaths per year

  Treatments - surgery, chemotherapy and radiotherapy

  Survival - 5 year survival 15% for stage 4
• ACT of melanoma using TIL

  Piece of melanoma is extracted and put into plates. T cells are grown in the plates with the tumour fragments to identify specific tumour recognition. The positive T cells are selected and expanded to 10^10 cells before it is put back into the patient

  
• ACT is unaffected by the size or location of the tumour but not worked in all patients

  
• Observations on objective clinical responses achieved by ACT from 1985 onwards


  • All ACT regimens were better than IL2 alone:

  Good - ACT

  Better - ACT + CHX / CHX + RTX

  ACT is effective irrespective of size and location of tumour
• Factors that correlate with responses in ACT

  • Persistence of T cells (up to 75% of T cells, 6-12 months)

  Age of T cells (telomere length)

  CD27 expression - marker of T cell differentiation - more expression, more less differentiated, younger T cells
• Best responses require lymphodepletion using chemo/radiotherapy
• Potential mechanisms for enhancement of ACT by chemotherapy and radiotherapy

  Combination of CHE and RAD is effective at lymphodepletion of the patient

  Transfer of T cells into an empty lymphoid compartment

  Depletion of suppressive Treg cells

  Depletion of other cells that compete for cytokines

  Damage to gut wall via RTX creates inflammatory environment

  Allows persistence and proliferation of T cells to maximise anti-tumour effect

  
• Lifileucel


  FDA approved Feb 2024
• Improving T cells for ACT by genetic modification


  • Specificity:

  TCR

  CAR
• TCR


  Naturally occurring Ag specific Rs

  Recognises short peptide fragment extracted from the IC environment of any cell when they are presented on a MHC

  From a CD8 T cell, it can recognise IC tumour Ags

  TCR genes can be transfection into other T cells and copper specificity

  Possibility of recombinant TCRs (mixed pair) and increasing affinity of original TCR via further engineering

  Sequencing of the TCR alpha and beta chains > viral vector encoding tumour specific TCR sequence for transfection

  
• CAR


  Artificial R that recognises cell surface tumour Ag

  Transfection of this R into any T cell allows recognition of tumour Ag and T cell activation

  Recognition is MHC independent

  Usually single chain variable fragment (scFV derived from mAb fused to CD3 zeta transmembrane and endodomain

  
• Improvement CAR T cells

  • Co-stimulation/activation genes:

  CD28

  CD137

  CD134

  CD278

  Suicide genes:

  Drug selection

  Death proteins

  Mab drug targets

  Activation and growth:

  Co-stimulators molecules

  Cytokine Rs
• Transferring TCR or CAR eliminates the need of using an array to identify specific tumour recognition
• Loss of control


  Large number of T cells could lead to loss of control where the T cell begins attacking self tissues and organs
• Development of autoimmunity after ACT in melanoma

  • Vitiligo, Uveitis
• Trial with CAR T cells CD19 in ALL, n=90 total and n=20 treated


  • 3 deaths by June 2016 via one of the following reasons:

  Brain damage

  Cytokine storm

  Toxic reaction between fludarabine and CAR T cells

  Trial resumed with no fludarabine, n=18

  2 more deaths by Nov 2016 due to similar reasons > trial suspended
• The T cells were specific Melan-A (protein) which is expressed on both healthy cells and cancer cells. Healthy cells with Melan-A were killed off
• Autoimmunity


  • Vitiligo, Uveitis

  
• Trial with CAR T cells CD19 in n=90 treated


  • 3 deaths in a month:

  Brain damage

  Cytokine storm

  Toxic reaction between fludarabine and CAR T cells

  Trial resumed with no fludarabine, n=18

  2 more deaths in a few months:

  Brain damage and cytokine storm

  Trial suspended, product redesigned
• FDA has approved kymriah CAR T cell) for BALL and DBCL in Aug 2017 and 4 more approved since
• Challenges for future development of T cell therapies

  • Cost:

  Expensive

  Customised biological therapy for each patient

  Labour intensive

  GMP grade tissue culture required

  Only applicable to a few cancers (currently due to lack of immune cell infiltration in tumours, it is rendered as ineffective in solid cancers)

  Logistics:

  Manufacturing delays - not feasible for patients in critical conditions

  Specialised hospital facilities - monitoring of patient for at least 1 week

  Side effects:

  Autoimmunity/off target effects - killing of cells in tissues that are unpredicted

  Cytokine storm - huge surge in production and release of pro-inflammatory cytokines > changes to the body and inference with normal cell function

  Neurotoxicity - memory loss

  Safety:

  Use of recombinant viruses:

  Secondary cancers?

  Use of cells grown in the laboratory

  
• Active research: Off switches, Increasing knowledge about T cells may allow further optimisation, Immune checkpoint inhibitors e.g. Abs against PD1 or activate pre-existing T cell responses
• Learning Objectives


  • Understand the normal role that T cells play in maintaining health.

  Understand the differences between the different approaches used for T cell therapy of cancer e.g. therapeutic vaccines vs adoptive cell therapy vs checkpoint inhibitors.

  Know the history of adoptive cell therapy for cancer using melanoma as a model.

  Know the different types of tumour antigens recognized by T cells.

  Understand how T cells that can be genetically modified to express TCRs or CARs for immunotherapy.

  Know some of the obstacles for adoptive cell therapies and the prospects for improvements.

  
• T cells


  Cells that are part of the immune system and help fight infection

  
• B cells


  Cells that are part of the immune system and produce antibodies