• History of Immuno-Oncology
• Types of Immunotherapy
• Immunomodulatory agents
• Personalized Cancer Vaccines
• CAR-T cell therapy
• Immune Checkpoint Inhibitors
• Focus: Immune Checkpoint Biomarkers
3. Evolution of Cancer Immunotherapy
• William Coley – 1890s surgeon
• Coley’s toxin…
• BCG, IFN-alpha, IL-2
• IL-2 applications in melanoma and RCC proved that advanced metastatic cancers can be
controlled in some patients by stimulating T cells with cytokines
• Critical development
• CTLA-4 shown to be inhibitory for T cell responses by James Allison and Jeff
• Ipilimumab (CTLA-4 inhibitor) the first ICI. Trials initiating 2000
• The “Breakthrough” – Allison and Honjo win 2018 Nobel Prize
8. Personalized Cancer Vaccines
First proposed by Paul Ehrlich in 1909
• Somatic mutations can generate cancer-specific neoepitopes that are recognized by autologous T
cells as foreign and constitute ideal cancer vaccine targets.
• Drivers and passengers
• Every tumor has its own unique composition of mutations, with only a small fraction shared
• Technological advances in genomics/proteomics (NGS, mass spectrometry), data science
(Bioinformatics), and cancer immunotherapy now enable the rapid mapping of the mutations
within a genome, rational selection of vaccine targets, and on-demand production of a therapy
customized to a patient’s individual tumor
• Both class I MHC (CD8+ CTLs) and class II MHC (CD4+ T helper [TH1] cells) immune responses are
10. Personalized cancer medicine
Ugur Sahin, and Özlem Türeci Science 2018;359:1355-1360
The broader impact of realizing
personalized mutanome vaccines
• Neoepitope vaccines should theoretically be
able to target all cancers.
• True patient-specific therapy
• A delicate interplay between the tumor and the
immune system (“cancer-immune set point”)
shapes each individual cancer
12. Adoptive T cell Transfer
Chimeric Antigen Receptor T cells (CAR-T)
• autologous T cells engineered to express a chimeric antigen receptor
(CAR) specific for the CD19 B lymphocyte molecule have recently
been approved by the U.S. Food and Drug Administration (FDA) for
treatment of refractory pre-B cell acute lymphoblastic leukemia and
diffuse large B cell lymphoma
• The first successful gene therapy.
16. T cells can kill cancer cells
• Tumors are immunogenic. Mutations represent “neo-antigens.”
• Certain cancers observed to contain TILs, but TILs were dysfunctional
• Dysfunction traced to the expression of multiple co-inhibitory receptors that
“block” the immune system’s ability to kill the cancer cell – termed “Immune
• Now know that antibody drugs that block these signaling molecules have the
ability to release the immune system to kill cancer cells
17. Mutational burden by tumor type
Imperfectly predictive of response to immune checkpoint blockade
Schumacher, Science, April 2015
19. PFS and OS of dMMR vs WT on
Le, NEJM, 2015
20. Based on data from 5 separate clinical trials involving 149 patients who were dMMR/MSI-H.
RECIST overall response rate 39.6%.
Responses exceeded 6 months in 78% of responders.
11 complete and 48 partial responses.
Response rate similar whether the patients were diagnosed with CRC or with other cancers.
22. Timing of clinical development of anti–CTLA-4, anti–PD-1, and anti–PD-L1
antibodies, from first administration to humans to FDA approval
Adapted from Antoni Ribas, and Jedd D. Wolchok Science 2018;359:1350-1355
*This class of agents was the first to be granted FDA approval on the basis of a genetic characteristic as opposed to the site of origin of the cancer, with the
approval of pembrolizumab and nivolumab for the treatment of microsatellite-unstable cancers of any origin in 2017
23. Resistance to Immune Checkpoint Inhibition
• Success in NSCLC, melanoma, Bladder Ca, RCC, HNSCC, Cervical CA
• Many encouraging responses, some apparent cures
• But most patients do not respond, and there is the potential of significant
=> Mechanisms of resistance?
=> Combination therapy approaches?
=> Predictive biomarkers?
30. Programmed Cell Death 1 (PD-1)
• a dominant negative regulator of antitumor T cell effector function
• an “immune checkpoint”
• PD-1 has two ligands
• PD-L1 (also known as CD274 or B7-H1)
• PD-L2 (also known as CD273 or B7-DC)
• PD-1 is a negative regulator of preexisting immune responses, which
becomes relevant to cancer because its blockade results in preferential
stimulation of antitumor T cells
31. Mechanism of action of PD-1–blockade therapy
Antoni Ribas, and Jedd D. Wolchok Science 2018;359:1350-1355
T cell activation
XT cells excluded
T cell activation
T cells infiltrate tumor
33. Role of IFN signaling
• IFN signaling pathway intact
=> response more likely
• IFN signaling altered or diminished
=> response less likely
Keenan, et al, Nat Med, 2019
34. Unmet Medical Needs in the Selection of
Immunotherapies - ICIs
• Issues with the selection of Immune Checkpoint Inhibitors
• Understanding why only small % respond initially => may guide combination IO therapy
• Alternative checkpoints engaged?
• Loss of HLA expression?
• Perturbations in IFN-g signaling?
• Understanding why some acquire resistance to ICIs and relapse
• Selection for “resistant” clones
• Disfavorable microbiome?
• Early identification of likely non-responders
• ICI therapy costs $150,000.00/year
• SAEs are fairly common and sometimes irreversible, or even life-threatening
• Multiple types of Immunotherapy
• Successful in part, but limited by resistance and toxicity
• Enormous potential seems clear
• Massive commitment by Pharma to IO drugs and technologies
• Complex interactions among tumor cells, immune cells, supporting stroma, gut
microbiome, and other host environmental factors offers possibilities for diagnostic
• Understanding how various Immune Checkpoints work independently and in concert to
evade host immunity is an important next step
Customizing a patient-specific cancer vaccine. Patient tumor biopsies and healthy tissue (e.g., peripheral blood white blood cells) are subjected to next-generation sequencing. By comparing the sequences obtained from tumor and normal DNA, tumor-specific nonsynonymous single-nucleotide variations or short indels in protein-coding genes are identified. A computational pipeline is used to examine the mutant peptide regions for binding to the patient’s HLA alleles (based on predicted affinity) and other features of the mutated protein deemed relevant for prioritization of potential vaccine targets. These data can facilitate selection of multiple mutations to design unique neoepitope vaccines that are manufactured under GMP conditions.
Personalized cancer medicine. Left: Conventional stratified medicine matches a patient to an existing off-the-shelf drug using biomarker assays. Right: As opposed to a preformed drug, mutanome vaccination is a patient-specific therapy that targets cancer mutations per se, irrespective of their primary sequence. Thus, mutanome vaccines may qualify as universal and tailorable therapy from which each cancer patient may benefit.
Timing of clinical development of anti–CTLA-4, anti–PD-1, and anti–PD-L1 antibodies, from first administration to humans to FDA approval. Thus far, there has been drug regulatory approval for six antibodies that block immune checkpoints and a combination of two immune checkpoint-blocking antibodies. The gray shading represents the period of clinical development for each of these antibodies, from the dosing of the first patient until regulatory approval (red circles) in different indications. HNC, head and neck cancer; RCC, renal cell carcinoma; MSI-h, high microsatellite instability; HD, Hodgkin’s disease; HCC, hepatocellular carcinoma; GEJ, gastroesophageal junction.
Mechanism of action of PD-1–blockade therapy. (Left) TCR recognition of the cognate antigen presented by MHC molecules on the surface of cancer cells results in T cell activation. T cells then produce IFN-γ and other cytokines. Cancer cells and other cells in the tumor microenvironment have IFN-γ receptors (IFN-γR) that signal through JAK1/2, which phosphorylate (P) and activate signal transducers and activators of transcription (STAT) proteins that dimerize and turn on a series of interferon-response genes, including interferon regulatory factor 1 (IRF-1), which binds to the promoter of PD-L1, leading to its surface expression. The reactive expression of PD-L1 turns off the T cells that are trying to attack the tumor, and these T cells remain in the margin of the cancer. (Right) Blockade of the PD-1–PD-L1 interaction with therapeutic antibodies results in T cell proliferation and infiltration into the tumor, inducing a cytotoxic T cell response that leads to an objective tumor response.