lung cancer immunotherapy Flashcards
Lung cancer overview
Lung cancer is the leading cause of cancer death and the second most common cancer in the world.
Lung cancer has an estimated incidence of 1.6 million new cases every year, 12.9% of the global cancer incidence.
For years the standard treatment strategies of lung cancer have been surgery, chemotherapy, radiation therapy and targeted therapy.
To date, surgery is the first choice treatment, but most clinically diagnosed cases are inoperable.
Chemotherapy and/or radiotherapy are the next options considered for such cases however these treatment modalities have adverse effects and are sometimes lethal to patients.
Thus, new effective strategies with minimal side effects are urgently needed.
Recently, tumour immunotherapy has attracted attention as a first line treatment for lung cancer.
2 types of LC
Two types:
Non small cell lung cancer (NSCLC)
80% of cases; can be eithersquamous cell carcinoma, or non squamous adenocarcinoma or large-cell carcinoma
Small cell lung cancer
less common type thatusually spreadsfaster than non-small-cell lung cancer
Causes of LC
Causes of lung cancer:
Smoking - over 85% of cases
Other causes of lung cancer: Exposure to cancer-causing chemicals Family history of lung cancer (genetic associations) High levels of air pollution High levels of arsenic in drinking water Radiation therapy to the lungs Asbestos
Incidence and prognosis of NSCLC
Lung cancer mainly affects older people.It’srare in people younger than 40, and the rates of lung cancer rise sharply with age. Lung cancer is most commonlydiagnosed in people aged 70-74.
Lung cancer treatment issues
Early-stage disease is potentially curable, although curative-intent surgery is only feasible in 25–30% of patients (in the USA) (PMID 27800034).
Squamous cell lung cancer (sqCLC) is an aggressive form of cancer. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities.
57% of patients have already distant metastatic disease at diagnosis with a 5-year survival rate of less than 5%.
10-35% of NSCLC patients have activating mutations in Epidermal growth factor receptor (EGFR). Targeted therapies against EGFR and other mutated genes have significantly improved outcomes for a molecularly defined subgroup of patients.
For the majority of patients platinum-based chemotherapy (e.g. Cisplatin, Carboplatin, Pemetrexed) is still the first-line therapy and provides an OS of 10 months.
New treatments are urgently required
Advantages and disadvantages of each conventional treatment form
Surgery: Potential cure for early stage lung cancer
dis: tumour cells may remain
Radiotherapy: Could be used as a intent to cure treatment for early NSCLC
but toxicity and poor outcomes for advanced disease
Platinum based chemo: Available as first line therapy, numerous combinations
Toxic and prone to tumour resistance
targeted therapy- Relatively effective against tumours with defined mutations
Not available for most lung cancer patients, tumours develop resistance
Immunotherapy: Specific tumour killing with potentially less toxicity. Lots of potential strategies
Dis: Development of autoimmune reactions, expensive
Describe the immune response to cancer
Interluekin-2
IL-2 is an essential cytokine in the proliferation of T-cells. Its been used as a cancer therapy since the 1980’s
Elimination
The Immune response targets and kills tumour cells
Equilibrium
Tumour cells survive but growth and metastasis are held in check by the immune system
Escape
Resistant tumour cells lead to clinically apparent cancers
Components of the host immune system that fight against tumour cells
Macrophages: Phagocytose tumour cells in a process called immunogenic cell death
NK cells: Take part in various cytotoxic immune responses
Dendritic cells: Infiltrate the tumour microenvironment and present antigen to T cells
Cytokines: Activate immune networks and cytotoxic immune responses against tumours
Chemokines: Recruit leukocytes to different regions
T cells: Involved in tumour elimination and co ordination of the immune response
B cells: Induction of antibody
Both innate and adaptive immune responses are involved in cancer immunology
Overall immune response to cancer
Myeloid-derived suppressor cells Cancer associated fibroblasts T-regulatory cells Tumour associated macrophages TGF-β VEGF
Lung cancer immunotherapy overview
Cancer immunotherapy: “harnesses the immune system as a therapeutic agent for cancer treatment” Immunotherapy can involve: Cytokines Cells Antibody Vaccines Oncolytic viruses Immune modulatory compounds (drugs, adjuvants)
Cytokines as immunotherapy? describe clinical trials
The first immunotherapies developed for NSCLC were recombinant cytokines.
These included IL-2 and interferon α (PMID: 1322167) which were found to be toxic and ineffective.
Initial phase II trials for IL-2 were not indicative of clinical benefit either.
A phase III trial of IL-2 with chemotherapy and hormone therapy reporting a 20% partial response and 50% stable disease among 20 advanced NSCLC patients.
A subsequent phase II trial showed that the addition of IL-2 to chemotherapy (gemcitabine plus docetaxel) in patients with advanced NSCLC improved responses rates with good tolerability (PMID: 19242101).
But these findings were not replicated in a phase III randomized trial of IL-2 in combination with chemotherapy with a cisplatin doublet (PMID: 21720704).
Cytokine therapy is very toxic. Cytokines used ex vivo are more promising.
Describe a type of adoptive cell therapy 1) CAR T cells
Chimeric antigen receptor (CAR) T-cells
Express a fusion protein with an antibody-derived targeting component and T cell activating component.
Promising data targeting CD19 for hematologic malignancies (Approved in 2017 for leukemia)
Antigen receptors to the tumour antigen mesothelin to target solid tumours including NSCLC.
EGFR-targeted CAR T-cells have been tested in a phase I trial of EGFR-positive NSCLC
CAR T-cells have yet to prove efficacious in solid tumours. They will likely select for tumour escape mutants.
Numerous antigen are being targeted for solid malignancies.
CEF, EGFR, FAP are all target antigens
Describe another adoptive cell therapy: CIK (cytokine induced killer cells)
Cytokine-induced killer (CIK) cells:
MHC-unrestricted cytotoxic lymphocytes generated/expanded ex vivo with IFN-γ, IL-2 and anti-CD3
CIK cells are cytotoxic effector T cells expressing CD3, CD56 and NKG2D
CIK cell therapy has showed significant survival benefits in a few NSCLC clinical trials
A Meta study found that CIK cell therapy significantly improved the objective response rate and overall survival The CIK cell combined therapy did not present any evidence of major adverse events in patients with NSCLC.
Describe lung cancer vaccines
Induce lasting immune responses in the patient. Based upon antigen/adjuvant combinations. Many types of vaccine: DNA/RNA Peptide Whole protein Viral vector Whole tumour cell Dendritic cell
During the last 20 years numerous efforts have been made to use vaccination to enhance anti-lung tumour responses against specific antigen.
Most studies have not been successful.
Whilst immunological responses are often observed they have rarely corresponded to clinical efficacy.
Why? – immune inhibition by tumours.
Combination of vaccines and other immunotherapy may result in improving vaccine efficacy.
(examples of trials on table)
Why haven’t vaccines worked for NSCLC
Vaccines have the potential to induce lasting immune responses with little cytotoxicity.
Why haven’t they worked for NSCLC?
They demonstrate a lack of clinically significant outcomes, despite their ability to prime and expand tumour antigen-specific T cells.
Inhibition by the tumour
Reduced antigenicity
Checkpoints
Immune suppressive cells
Loss of antigen
More recent vaccines regimens are beginning to consider these factors
Development of checkpoint inhibitors
A breakthrough for Immunotherapy Now licenced by the FDA for use against various tumours: Metastatic melanoma (2015) NSCLC (2015) Renal cell carcinoma (2015) bladder cancer (2016)
“Lung cancer—for so long, the poster child of failed trials—has seen tremendous advances in the last decade. Immunotherapy, previously only considered a promising concept, is now front and centre news as a therapeutic reality in the treatment of advanced NSCLC”.
Checkpoint inhibitors have significantly improved outcomes in patients with metastatic NSCLC and are currently an established second-line therapeutic option.
Two programmed death-1 (PD-1) inhibitors named nivolumab and pembrolizumab have been approved by the Food and Drug Administration (FDA) to treat metastatic disease in second line.
Pembro approved as first line therapy for tumours with 50% PDL-1.
Several clinical trials are ongoing to expand the use of checkpoint inhibitors including in the refractory or front line setting:
As first line therapy
In combination with anti-CTLA4 antibodies.
In combination with chemotherapy, radiotherapy and vaccines
Describe the checkpoint inhibitor PD-1
PD-1 is expressed on T-cells
Limits the onset of autoimmunity during inflammation
PD-L1 and PDL-2 are expressed on antigen presenting cells and switch off T cell activation
Tumour cells express PD-L1 to inhibit anti-tumour immune responses
Describe the checkpoint inhibitor nivolumab
Randomized, open-label, international phase 3 study of non squamous NSCLC patients who had progressed during or after platinum-based doublet chemotherapy:
Nivolumab OS 12.2 months
Docetaxel OS 9.4 months
Randomized, open-label, international phase 3 study of squamous NSCLC patients who had progressed during or after platinum-based doublet chemotherapy:
Nivolumab OS 9.2 months
Docetaxel OS 6 months
Describe the checkpoint inhibitor pembrolizumab
Randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells:
- 5 months with docetaxel.
- 4 months with pembrolizumab 2 mg/kg
- 7 months with pembrolizumab 10 mg/kg
Phase III trial for Pembrolizumab as first line therapy for PDL-1 expressing tumours:
10.4 months PFS with Pembrolizumab 200mg/kg
6 months PFS with platinum based doublet chemotherapy
Checkpoint inhibitor CTLA-4
T cells require two activating signals
Peptide-HLA
Co-stimulation of CD28-B7/B8
Activated T-cells express CTLA-4 which binds B7/B8 with far greater affinity than CD28
This inhibits T-cell activation
TGF-β expression by tumour cells upregulates CTLA-4 on T cells.
Problems with checkpoint inhibitors: They’re very expensive
They do not work in some cancer patients (PMID: 27532023)
Toxicity
Autoimmune phenomena, especially combination checkpoint inhibitor therapy.
Treatment-related adverse events reported in phase II/III trials of checkpoint inhibitors in non-small cell lung cancer.
Role of the gut microbiome in immune responses
The types of bacteria in the intestine correlate with checkpoint receptor efficacy
Certain types of bacteria are associated with response
Bifidobacterium
Lactobacillus
Others
Mechanism of action is unknown however may involve dendritic cell activation, Th1 immune responses and microbial metabolites. Colitis is a marker of checkpoint inhibitor efficacy.
Currently FMT is being studied to determine whether it can improve CPI efficacy.
Combination therapy
The combination of drugs/immunotherapy acting through different mechanisms to inhibit/enhance the same process is the basis for immunotherapeutic combinations with synergistic effect.
Chemotherapy - Immunotherapy
Immunotherapy – Immunotherapy
E.G Phase I study in patients with NSCLC (NCT01454102) comparing nivolumab (checkpoint inhibitor) as monotherapy or combined with:
Chemotherapy (Gemcitabine/cisplatin/Carboplatin),
Targeted therapy (Erlotinib - EGFR inhibitor or Bevacizumab – VEGF inhibitor)
Checkpoint inhibitor (Ipilimumab – anti-CTLA4).
Vaccine – chemotherapy/Radiotherapy Vaccine – checkpoint inhibitor Reduced antigenicity Checkpoints Immune suppressive cells Loss of antigen Some combinations can be antagonistic rather than synergistic Combinations may also synergise to increase adverse effects and toxicities
Potential advances and future challenges
Potential advances:
Biomarker discovery to select patients that may respond to a particular therapy
Combination therapy rendering checkpoint inhibitors less toxic, more efficacious and cheaper
The development of CAR T-cells against NSCLC
Combination therapy with vaccination, chemotherapy and immune modulation
Personalised vaccination and neo-antigen
Tackling the Tumour microenvironment (TME)
Harnessing intestinal immunity to target cancer
Future challenges Costs of therapy Toxicity Increasing incidence of lung cancer Lung cancer epidemic in China
