cancer immunotherapy

for decades thought that tumor is not detected by the immune system

but TCR-transgenic mice argue against it -> any tumor detected by the immune system

TCR transgenic mice TCR MHCI restricted & OVA-specific

B16-OVA injected subcutaneous -> mouse melanoma B16 transfected with OVA

B16 non-immunogenic tumor: not able to efficiently prime CD8 cells

local & tumor-specific CD8 proliferation

nothing if only B16 -> tumor-specific priming of CD8+ T-cells in the DLN

cross-presentation process -> Ag in tumor -> class I presentation from extracellular Ag OVA

discrepancy: still observe uncontrolled like growth -> tolerance

no signal 2 —> DC not activated

induce tumorigenesis by injecting compounds inducing mutations -> long process as it starts from 1 transformed cell

most don’t develop tumor -> induced tumor immunogenic

if treated with antiCD4/CD8/IFNγ (block important immune effectors) -> most mice develop a tumor

activates immune system -> helps to control/cure the tumor

also in humans but tumors not detected due to control/cure

Elimination

Equilibirum

Escape

cancer immunosurveillance

killing of tumor cells due to innate & adaptive immunity

can be supported by cancer immunoediting

cancer persistence / dormancy

acquisition of mutation not detected

some tumor cells persist

Genetic Instability & immunoselection

spontaneous regressions in patients associated with immune responses against the tumor

observed by clinicians

CD8+ T-cell infiltration in the diagnosis biopsy is of good prognostic

high infiltration of CD8 -> respond to treatment induced tumor cell death & contribution of CD8

infuse anti-tumor T-cells expanded in vitro into patients

mount an immune response against the tumor into the patient

boost the ongoing spontaneous immunity against the tumor

recombinant TLR ligand, anti-CD40 (improve signal 2)

block immune checkpoints on exhausted T-cells (anti-CTLA4 / anti-PD1)

induce a de novo immune response by vaccinating with tumor antigens

neoantigen

• ideal case, viral proteins for virus-induced tumors (papillomavirus)

• Gardasil prophylactic vaccine for cervix cancer

• antigens not present in healthy cells -> no tolerance against them

• mutated proteins: mutation creates an epitope for CD4/CD8 but difficult as patient-specific

tissue specific antigen

• with or without an upregulation compared to healthy cells

• melanoma: enzymes implicated in pigment synthesis (tyrosinase)

• works fine but risk to destroy all melanocytes with melanoma

• vaccination against pigment enzyme induces also auto-immune disease

need signal 1 (antigen) & signal 2

should contain T CD8+ & T CD4+ epitopes

full protein: sometimes complicated to produce at large scale

plasmids coding for the protein

peptides: easy to produce but HLA restriction

->needs to be loaded -> half of population HLA2.1+ -> can treat 50%

long-term delivery = depot at the injection site (oil)

induce signal 2: TLR ligand, CpG (TLR9)

tolerance in patients

solution: passive immunotherapy

surgical resection of the tumor

isolation of TIL

selection of tumor-reactive T-cell clones

propagation of tumor-reactive T-cell clone

reinjection into the patient

clonal dilution & select tumor-reactive

clones

apply mitogen & expand massively

Collection of peripheral blood lymphocytes

antigen-specific stimulation & propagation of tumor-reactive T-cells

no tumor antigen selection

expand massively the whole population with tumor-specific antigen

Sipuleucel

DC from patient blood loaded with prostate-specific antigen & reinjection

longer follow-up showed that it had no effect

10% is the maximal difference but a highly expensive drug

anti-PD1

blocks interaction with PDL1 & L2

works compared to chemotherapy Dacarbazine in metastatic melanoma

long-term patients without detection of tumor (cure/control) achieved in 20% of patients

research in finding biomarkers for responders

Rituximab (anti-CD20) for B-cell lymphoma

chimeric Ab depleting B-cells

gain 20% of living patients after 3 years

standard therapy: 4 drugs but low responses (60% dead after 3 years)

identify a T-cell clone with high affinity & cloning of the 2 chains

transduce in naive T-cells -> make T-cells more efficient

but T-cell senescence: don’t dived anymore at some point

patient-specific

treatment, not much used

universal TCR, no HLA restriction

escape patient specificity/MHC restriction

recognizes Ab (tumor-specific) in a single molecule

3 ITAM motifs: single chain fragment variable

make a short form of Ab -> Vh & K domain with the linker to keep Ab reactive

transduce in patient cells & reinjection but not optimal -> no signal 2

1. generation: activation only

2. generation: dual signaling -> cytoplasmic sequences from costimulatory sequences, first patient died from response due to cytokine storm

3. generation: multiple (>2 signals) combine costimulatory sequences

doesn’t work well for solid tumors -> difficult to access tissue after injection but good form blood cancers

cancer progression

expression of immunosuppressive factors like TGFß/IL-10 or PD-L1

Trg & other immunosuppressive cells infiltrate

stop codon introduced -> no class 1 expression

get rid of all cytotoxic T-cells

NK cells are not good enough