Immuno Exam 2: Immunotherapy for the Treatment of Cancer

3 phases of cancer development

1. elimination

2. equilibrium

3. escape

goal of immunotherapy for cancer

to educate and liberate underlying anticancer immune response in the adaptive immune system

passive immunotherapy

Antibodies or other immune system components that are made outside of the body and administered, to help them fight off cancer

active immunotherapy

Aim to stimulate effector functions of the immune system itself

goals of cancer immunotherapy

-augment the pt's own immune system to fight cancer

-overcome the mechanisms that tumors evade and suppress immune response

3 ways we can augment the pt's own immune system to fight cancer

-activate the immune system

-inhibit immunosuppression

-avoid autoimmunity

MOA of non-specific immune stimulants

rev up immune system response to all types of pathogens

examples of non-specific immune stimulants

BCG (bacillus Calmette-Guerin)

IL-2

interferon

function of naked monoclonal antibodies

bind to antigens that there are more of on the surface of cancer cells than healthy cells

MOA of monoclonal antibodies

-boost immune response against cancer cells

-block proteins that help cancer cells grow

4 ways that monoclonal antibodies boost immune response against cancer cells

-induced programmed cell death

-antibody dependent cellular toxicity (ADCC)

-complement-dependent cytotoxicity (CDC)

-antibody dependent cellular phagocytosis (ADCP)

what are conjugated monoclonal antibodies (chemotherapy)

monoclonal antibodies covalently linked to small molecular cytotoxic (chemotherapy) drugs that focus on specific cancer cell to reduce total systemic toxicity

is a mAb joined to chemotherapy

MOA of conjugated monoclonal antibodies

- mAb targets a specific cancer antigen while not harming healthy cells

◦ Potent cytotoxic small molecular agent with high systemic toxicity

◦ induces cell death after being internalized in the tumor cell and discharged from mAb

◦ Linker stable in circulation which releases the drug in neoplasms

◦ Induces higher tumor selectivity while improving the tolerability of the drug

MOA of conjugated monoclonal antibodies joined to radiotherapy

◦ Antibodyguides the radiation to the target cell

◦ Radiation also kills neighboring cancer cells that do not express the antigen, "crossfire" effect

4 limitations with monoclonal antibodies

-ADEs

-conjugated mAbs have chemo or radiation SFX

-don't work well on bulky tumors ( only access surface antigens)

-not curative- cancer develops resistance to the drug

what does BiTE stand for

bispecific T-cell engager

structure parts of BiTE antibodies and their functions

2 antibodies of interest are joined via amino acid linkage

◦ One domain interacts with T-cell

◦ One domain interacts with the desired tumor associated antigen (TAA)

MOA of BiTE antibodies

◦ T-cell perforates the tumor cell membrane

◦ Releases granzymes that induces caspase mediated apoptosis

◦ Releases cytokines

◦ Induce T-cell proliferation

major ADE of BiTE antibodies

cytokine release syndrome

4 limitations with BiTE antibodies

-cytokine release syndrome

-immune effector cell-associated neurotoxicity syndrome (ICANS)

-may need inpatient admission for observation with initial dosing to manage side effects

-many are only FDA accelerated approval

grade 1 CRS (mild)

Fever >/= 38C

grade 2 CRS (moderate)

-fever with hypotension not requiring vasopressors

or

-hypoxia requiring nasal canula

grade 3 CRS (severe)

-fever with hypotension requiring vasopressor

or

-hypoxia requiring high flow nasal canula

grade 4 (life threatening)

-fever with hypotension requiring multiple vasopressors

and/or

-hypoxia requring positive pressure ventilation

MOA of cytokine release syndrome (CRS)

-stimulus causes lysis of immune cells

-this activates macrophages and DCs

-release of pro-inflammatory cytokines

-ends in a + feedback loop

prevention of CRS

• premedications (corticosteroid, acetaminophen, diphenhydramine)

• Step up dosing (titrate up slowly)

what to do if CRS still occurs with preventative measures

Hold therapy until symptoms resolve, continue with premedication for next cycle and close monitoring inpatient

when to discontinue therapy in CRS

grade 4 or recurrent grade 3 toxicity

2 general pharmacologic treatments of CRS

• Corticosteroids

tocilizumab

MOA of immune checkpoint inhibitors (ICI) with CTLA4

blocks the binding of B7-1/B7-2 (on APC) to CTLA4 (on TC) which allows the T cells to be active and kill tumor cells

functions of checkpoint proteins

help keep the body's immune responses in check

T cells can be activated when...

• T-cell receptor (TCR) binds to antigen and MHC on the APC

AND

• CD28 binds to B7-1/B7-2 on the APC

when are T cells inactive and not able to kill tumor cells

with the binding of B7-1/B7-2 to CTLA4

MOA of immune checkpoint inhibitors (ICI) with PDL1/PD1

blocks the binding of PD-L1 to PD-1 which allows the T cells to stay active and kill tumor cells

PDL-1 vs PD-1 and function

PDL-1 is on tumor cells and PD-1 is on T cells

-the binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (regulation of immune system)

how do you explain immune checkpoint inhibitors to patients

Gas and brake pedal analogy

◦ Pressing the gas pedal = restoring T-cell activity and starting immune response against tumor

◦ Brake pedal = immune checkpoints will inhibit T-cell activity so we want immune checkpoint inhibitors (cutting breaks)

high PD-L1 expression

-PD-L1 is a biomarker

-high amount --> improved response rates, progression free survival, overall survival

MSI-H (microsatellite instability-high) as biomarker for ICIs

high MSI-H --> higher mutational burden--> upregulated expression of programmed cell death -1 (PD-1) and its ligand (PD-L1)

-MSI-H/dMMR predictive biomarker for immune checkpoint blockade in different cancer types

what is irAE

immune related adverse effects

side effect of immune checkpoint inhibitors

irAEs of CTLA-4

colitis and thyroiditis

irAEs of PD-1

pneumonitis and thyroiditis

timing and speed of treatment of irAEs

early recognition and prompt intervention critical for effective management and optimal clinical outcomes

why do ICI's cause irAEs? (2 functions)

-ICIs promote activation and expansion of T cells

-ICIs can affect any organ due to ability of T cells infiltrating most organs

monitoring parameters for immune related AEs

how are hypothyroid and endocrine irAEs managed

with hormonal supplementation without steroids

what's the main treatment of most irAEs

corticosteroids

tapering of cortidosteroids for treatment of irAEs

taper off of them for >4 weeks once symptoms resolve

patients with a pre-existing autoimmune condition and ICIs/irAEs

◦ higher risk of exacerbating underlying condition

◦ Allows for dose of prednisone < 10 mg daily (more could interfere with ICI efficacy)

management and ICI therapy of grade 1 irAEs (asymptomatic or mild)

observation

continue ICI with close monitoring

management and ICI therapy of grade 2 irAEs

-0.5-1mg/kg/day of prednisone or equivalent

-temporary hold on ICI; resume when grade

management and ICI therapy of grade 3 irAEs

management:

-treat inpatient

-1-2mg/kg/day of prednisone or methylprednisone

-if no response in 48-72 hours consider additional therapy

ICI: temporary hold until grade 1 or less of reaction

management and ICI therapy of grade 4 irAEs

management;

-treat inpatient +/- ICU

-1-2mg/kg/day of prednisone or methylprednisone

-if no response in 48-72 hours consider additional therapy

ICI: permanent discontinuation

exception: endocrinopathies managed by hormone replacement

pseudoprogression with ICIs

tell the patient this is normal

disease can get worse (due to inflammation and TC infiltration of tumors) before getting better

what type of therapy are chimeric antigen receptors (CAR)

adoptive T cell therapy

6 steps for CAR T-cell therapy

1. leukapheresis: blood drawn and T cells and removed, rest of blood is returned

2. collected TCs are sent to lab and receptors are added to create patient-specific CAR T-cell therapies

3. pt prepares for CAR TC therapy by getting low dose chemotherapy

4. infusion of pt's programmed T cells

5. monitor for side effects

6. continues monitoring for side effects and response to therapy

4 limitations of CAR-T cell therapy

1. antigen loss- cancer cells decrease antigen expression

2. T-cell exhaustion- fail to provide long-term protection

3. on-target/off-target tumor effect- B cell depletion

4. toxicities (acute or delayed)

what can CAR TC therapy cause

it can cause CRS (cytokine release syndrome) and ICANS (immune effector cell-associated neurotoxicity syndrome)

types of acute CAR TC toxicity

1. CRS

2. neurotroxicity

-immune effector cell-associated encephalopathy (ICE)

- immune effector cell-associated neurotoxicity syndrome (ICANS)

delayed CAR TC toxicities

-prolonged cytopenias

-opportunitistic infections

-on-target but off-target tumor effect

-B cell aplasia

-hypogammaglobulinemia

management of grade 1 CRS with CAR TC therapy

Tocilizumab: consider if CRS > 3 days with significant symptoms &/or morbidities

Supportive Care: antibiotics, G-CSF if neutropenic, symptomatic management

management of grade 2 CRS with CAR TC therapy

Tocilizumab: 8 mg/kg IV over 1 hour, may repeat in 8 hrs, no more than 3 doses/24 hrs

Corticosteroids: for persistent refractory hypotension after 1-2 doses of tocilizumab

Supportive Care: add vasopressors for refractory hypotension, transfer to ICU, hemodynamic monitoring

management of grade 3 CRS with CAR TC therapy

Tocilizumab: same as grade 2

Corticosteroids: dexamethasone 10 mg IV every 6 hours

Supportive Care: transfer to ICU

management of grade 4 CRS with CAR TC therapy

Tocilizumab: Yes as with grade 2

Corticosteroids: dexamethasone 10 mg IV every 6 hours. If refractory, consider methylprednisolone 1000 mg/day IV

Supportive Care: ICU care

management of neurotoxicty with CAR TC therapy grade 1 (with and without CRS)

no CRS: supprtive care

w/ CRS: tocilizumab

management of neurotixicty with CAR TC therapy grade 2 (with and without CRS)

no CRS

-supportive care

-dexmethasone 10mg IV q6 hours or methylprednisone 1mg/kg q 12 hours

w/ CRS

-tocilizumab

-consider ICU

management of neurotoxicty with CAR TC therapy grade 3 (with and without CRS)

no CRS:

-ICU

-dexamethasone 10mg Iv q 6h or methylprednisone 1mg/kg q 12 hours

-CT or MRI q 2-3 days if persistent

w/ CRS

-tocilizumab

-consider ICU

management of neurotoxicty with CAR TC therapy grade 4 (with and without CRS)

no CRS:

-ICU, consider ventilation

-high dose steroids

-CT or MRI q 2-3 days

-treat seizures

w/ CRS:

-tocilizumab

-consider ICU

pros and cons of tocilizumab

pro: Early administration may prevent high-grade CRS while maintaining efficacy of CAR T-cell therapy

con: early administration may predispose to neurologic toxicity

-Does not cross blood brain barrier and may increase IL-6 concentration in the

CNS

pros and cons of corticosteroids in CAR TC toxicities

con: high dose can decrease efficacy of CAR TC therapy

pro: reduced neurotoxicity if recieved at grade 1 vs more severe grades

function of therapeutic cancer vaccines

§ Increase presentation of tumor-associated antigens (TAAs) to the immune system

§ Increase activation of tumor-specific T cells and B cells

MOA of therapeutic cancer vaccines (example of prostate cancer vaccine)

1. pt's peripheral blood cells + APCs + TCs are harvested

2. harvested cells cultured ex vivo with recominant fusion protein composed of prostatic acid phosphatase and GM-CSF)

3. mature APCs reinfused into the patient to stimulate CD4+ and CD8+ cells

4. triggers immune response against cancer cells

treatment course of cancer vaccine

• 3 doses administered at 2 weeks interval

• Each dose is manufactured 3 days prior to infusion

• 1st infusion primes the anti-tumor immune response

• Subsequent 2 infusions boost the response

T-VEC (talimogene laherparepvec, Imlygic)

-first in class oncolytic immunotherapy

-contains a genetically modified version of herpes simplex virus that can selectively replicate in the tumor and cause cell destruction

-contains a gene for granulocyte-macrophage colony stimulating factor (GM-CSF) to attract dendritic cells once the rupture of cancerl cells releases tumor-derivced antigens

all together stimulates a system-wide immune response