Effective immunotherapy i.e. enlisting the patient’s own immune system to fight disease may mark a milestone in the fight against certain cancers. Three lymphocytes – T cells, B cells and NK-cells – involved in specific immune responses against cancers and other diseases. T cells recognize specific antigens via a T-cell antigen-receptor. The two main types of T cells, CD4- and CD8 T-cells, are categorized according to their respective CD4 and CD8 surface markers. The latter group includes cytotoxic T cells, also known as killer T lymphocytes. These cells kill invading pathogens or other disease-causing agents. Scientists discovered that a type of protein receptor, cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), prevented T cells from launching immune attacks [1]. In the early 1990s, another “brake” was discovered in dying T cells namely programmed death 1 or PD-1. The rationale underlying cancer immunotherapy is that exposing CTLA-4, PD-1 or using other appropriate immune-system-based therapies may enable the activation of the immune system to destroy cancer. Genetically engineering a patient’s T cells to target tumor cells marked one of the promising turning points in cancer immunotherapy, particularly for certain blood cancers and solid tumors. Melanoma and lung cancer, two often-fatal diseases, are treatable in the early stages with surgery or other standards of care. However, some patients are diagnosed during the later stages of the disease or relapse with refractory/unresectable tumors. For these subgroups, the latest National Comprehensive Cancer Network (NCCN) tailored algorithms coupled with systemic treatment options, including immunotherapies, could potentially improve outcomes. Here, I summarize the latest approved immunotherapies mentioned in the NCCN guidelines, along with other examples of investigational agents such as monoclonal antibodies, cancer vaccines, and natural killer cells. Additional examples of targeted therapies, novel “druggable” and other immunotargets are presented in the section, ”Future Directions.” Reference 1. Couzin-Frankel, J., Breakthrough of the year 2013. Cancer immunotherapy. Science, 2013. 342(6165): p. 1432-3.

1. Cancer Immunotherapies
Zeena Nackerdien

2. Helping the immune
system work better at
destroying cancer
cells
Stopping or
slowing the
growth of cancer
cells
Stopping cancer
from spreading to
other parts of the
body
Goals of Cancer Immunotherapy (1)
• Allow the immune
system to destroy the
cancer cell
• Prevent cancer cells from
growing rapidly
• Diagnose cancer
• Carry drugs directly
to cancer cells
• Deliver radiation
directly to cancer
cells
1. American Society of Clinical Oncology. Cancer.net.
http://www.cancer.net/navigating-cancer-care/how-cancer-treated/
immunotherapy-and-vaccines/understanding-immunotherapy.

3. Types of Cancer Immunotherapies (2)
GM-CSF, granulocute-macrophage colony-stimulating factor; OV, oncolytic viruses
2. American Cancer Society. Types of Cancer Immunotherapy. 2014
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-types.
3. Bartlett DL, Liu Z, Sathaiah M, et al. Oncolytic viruses as therapeutic cancer vaccines. Mol Cancer. 2013;12(1):103.
Different types are used for various
treatments
Monoclonal antibodies
Prime/boost vaccines used alone
or with adjuvants
Cancer vaccines
General anti-cancer stimulus/boost
another immunotherapy
Non-specific immunotherapies &
adjuvants
Cytokines (Interleukins,interferons,
GM-CSF)
Immune checkpoint blockade e.g.,
anti-CTLA-4 & anti-PD-1 agents
Other immune system boosters e.g.,
Imiquimod, thalidomide, BCG
Preventive (HPV, HBV)
Therapeutic
(Sipuleucel-T [Provenge®])
Investigational therapeutic OVs
armed with immunostimulatory
Genes (3)
Naked (general immune system boost/
target checkpoints/block cancer signals)
Conjugated to radiolabel/cytotoxic
agent
Bispecific (binds to 2 different proteins
e.g., CD19 & CD3)

4. Selected Therapeutic Mabs (targets) approved/review in EU
and USA (4)
4. Reichert J. http://www.antibodysociety.org/news/approved_mabs.php.
Necitumumab (EGFR)
NSCLC
Nivolumab (PD-1)
Melanoma,
NSCLC
Pembrolizumab (PD-1)
Melanoma
Iplimumab (CTLA-4)
Melanoma
Dinutuximab (GD2)
Neuroblastoma
Blinatumomab (CD19, CD3;
Murine bispecific tandem scFv)
ALL
Ramucirumab (VEGFR2)
Gastric cancer
Obinutuzumab (CD20)
CLL
Ado-trastuzumab-emtansine
(HER2)
Breast cancer
Pertuzumab (HER2)
Breast cancer

5. National
Comprehensive Cancer
Network (NCCN)
Guidelines
Melanoma & lung cancer

6. Why focus at first on melanoma and lung cancer? (5-9)
Melanoma
 Rising over last three decades
 80% of 66,000 annual skin cancer
deaths across the globe (5)
 <2% of all skin cancer cases in the
USA (2015: ~73,870), but causes
most (~9,940) related deaths (6,7)
 BRAF mutations identified in ~50%
of advanced melanoma cases (8)
 Immune checkpoint blockade
Lung cancer
 One of the leading causes of cancer-
related deaths
 Most common cancer worldwide (~14.1
million cases in 2012) (9)
 ~13% of all cancer cases in the USA
(2015: 221,200) (5)
 Most pts. diagnosed with stage IV
disease (refractory to standard
treatment) [reference]
 Multiple driver oncogenes
 Immunotherapies focus on tumor-
specific antigens/immune checkpoints
e.g., CTLA-4, PD-1
5. Lens MB, Dawes M. Br J Dermatol. 2004;150(2):179-85.
6. American Cancer Society. http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics.
7. American Cancer Society. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf.
8. Ascierto PA, Grimaldi AM, et al. Journal of Translational Medicine. 2014;12:277.
9. World Cancer Research Fund International. Worldwide data. 2014 http://www.wcrf.org/int/cancer-facts-figures/worldwide-data.

7. NCCN guidelines for treatment of advanced melanoma (10)
Laboratory workup, staging via
biopsy/imaging e.g, CT, PET-CT,
MRI, X-rays
Lymph node dissection, clinical
trial, local therapy options e.g.,
local ablation,
regional/systemic therapy
Clinical
trial/observation/systemic
therapy/palliative
resection/RT/best supportive
care
1st/2nd-line chemoa & targeted
therapies based on BRAFV600
status, incl. immune blockade;
best supportive care
10. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.
http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf

8. NCCN guidelines for treatment of advanced lung cancer (11-13)
Screening & staging disease/smoking cessation
counseling/pharmacotherapy/chemistry
profile/bronchoscopy/imaging (tailored to cancer
type e.g., SCLC/NSCLC
Surgery/preoperative/concurrent/definitive
chemoradiation/induction or palliative
chemotherapy/RT/local therapy of lung
lesion/mediastinal lymph node evaluation
Based on locoregional
recurrence/distant metastasis/EGFR or
ALK mutational status
1st/2nd-line chemoa & targeted
therapies based on type of lung
disease (NSCLC/SCLC), best supportive
care
11. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Lung cancer screening. Version 1.2016http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf.
12. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-Small-Cell Lung Cancer. Version 7.2015 http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
13. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Small-Cell Lung Cancer. Version 1.2016 http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.

9. Cancer vaccines

10. FDA-approved & investigational cancer vaccines (14)
Preventive√
• Gardasil® & Cervarix® (HPV 16 &
18)
• HBV vaccine
Therapeutic√
• Provenge® (selected pts. with
metastatic prostate cancer)
Vaccine platforms
• Vectors (bacterial/viral)
• With TLR
agonists/adjuvants/radiation
Oncolytic/oncotropic
viruses
• Ds DNA e.g., Reoviridae (T3D)*
• Ds/ss DNA e.g., Hepadnaviridae
• Ss DNA e.g., Retroviridae
• Ds RNA e.g., Birnaviridae
• Ss RNA e.g., Paramyxomaviridae
>effective in
combination
therapy
*investigational live reovirus type 3 strain; ds, double-stranded; HBV, hepatitis B virus;TLR, toll-like receptor; ss, single-stranded
14. National Cancer Institute. Cancer Vaccines. http://www.cancer.gov/about-cancer/causes-prevention/vaccines-fact-sheet#q5.

11. Oncolytic viruses (OVs) ─ Mechanism of action (3)
OV replicates
selectively in
tumor and/or
stromal cells
Dying cells
release “eat
me” or
danger
signalsRecognition
of ICD, DC
maturation &
TAA cross-
presentation
Antitumor
response
Tumor
eradication
CTL
Th
Treg
CTL
Th
NK
NKT
3. Bartlett DL, Liu Z, Sathaiah M, et al. Mol Cancer. 2013;12(1):103.

12. Outcomes of phase III vaccine trials (15)
DERMA
15. Kissick HT, Sanda MG. Current Opinion in Immunology. 2015;35(0):15-22.
MAGRIT
Tecemotide/SMART
IMA-901
Provenge/IMPACT
gp100
STn-KLH
Melanoma; GS* suggests
active immune response
Lung; GS* suggests active
immune response
Lung; +
OS (30.8 vs 20.6, p = 0.016)
Kidney;multiple-epitope response,
p=0.023
Prostate;↑OS in 28.5% pts;
Ab titer >400
Ph II & III: No correlation w. immune activity
Median or greater IgG response. OS 39.6 vs 25.4, p = 0.005

13. Non-specific cancer immunotherapies (NSCIs) & adjuvants (2)
BCG
Cytokines
Bacille Calmette-Guérin (germ for
bladder cancer mgmt.)
Immunomodulators
NSCIs & adjuvants
PD-1/PDL-1
Drugs
targeting
immune
checkpoints
2. American Cancer Society. Types of Cancer Immunotherapy. 2014:
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-types.
IL-2 IFN-
GM-CSF
CTLA-4 e.g., Ipilimumab
(Yervoy®)
e.g.,Pembrolizumab
(Keytruda®)
Thalidomide (Thalomid®),
lenalidomide (Revlimid®),
pomalidomide (Pomalyst®),
Imiquimod (Zyclara®)

14. PD-1/PDL-1 inhibitors

15. Tumor cells and dendritic cells: PD-1 & CTLA-4 immune
checkpoints (16)
16. Ott PA. http://www.onclive.com/publications/contemporary-oncology/2014/February-2014/Immune-Checkpoint-Blockade-in-Cancer-Inhibiting-CTLA-4-and-PD-1PD-L1-With-Monoclonal-Antibodies.
T-cell
Tumor cell
CTLA-4 B7,1/2
CD28 B7,1/2
T-cell
receptor
MHC
Peptide
PDL-1
PD-1
Peptide
MHC
PDL-1
PD-1

16. 0% response in
mismatch-repair proficient
colon tumors
62%response in
mismatch-repair deficient
colon tumors
Potential biomarkers predictive of tumor response to anti-
PD-1 agents (17)
60%response
in mismatch-repair
deficient, non-
colorectal cancers
Mismatch repair status may guide selection of patients with colon cancer for pembrolizumab therapy.
17. Helwick C. The ASCO Post [Internet]. 2015; 6(10). http://www.ascopost.com/issues/june-10,-2015/mismatch-repair-deficiency-predicts-benefit-with-pembrolizumab-in-colorectal-cancer.aspx.

17. Problems in designing clinical trials (18)
 Maximal tolerated dose and tumour response rates
 Insufficient understanding of the mechanism of action of immunotherapies
 Compared to classic chemotherapy it usually takes a prolonged period of time for
immunotherapy to achieve clinical efficacy, with even initial transient tumour
progressions having been observed
 The biology of disease should allow a relevant immune response to develop,
which may exclude patients in whom a quick tumour shrinkage is indicated
 Although some progress has been made in the development of immune
monitoring assays, these assays have not shown consistent results among trials
and they have not been validated
18. Lesterhuis WJ, Haanen JB, Punt CJ. Nat Rev Drug Discov. 2011;10(8):591-600.

18. Approved/investigational anti-PD-1/L-1 agents (19)
Nivolumab (IgG4 fully human
AB/BMS-ONO)
Pembrolizumab (IgG4
engineered humanised AB,
Merck)
MPDL3280A (IgG1 engineered
fully human AB,
Genentech/Roche)
MEDI4736 (IgG1 engineered
fully human AB, MedImmune)
Pidilizumab (IgG1k humanised
AB, CureTech)
BMS936559 ( (IgG4 fully
human AB, BMS-ONO)
MSB0010718C (IgG1 fully
human AB, Merck Serono)
19. Homet Moreno B, Ribas A. British Journal of Cancer. 2015;112(9):1421-7.

19. Selected anti-PD1 trials in pts. with advanced melanoma (20)
Nivolumab (Phase 3)
Pidilizumab (Phase 2)
• ORR, 40
• Median PFS, 5.1 mo.
• 1-year OS, NR
• AEs*, 11.7%
• ORR, 32
• Median PFS, NR
• 1-year OS, NR
• AEs*, 9%
• ORR, 21 (2mg/kg)
• ORR, 25 (10mg/kg)
• Median PFS, 2.9 mo. (2mg/kg)
• Median PFS, 2.9 mo. (10 mg/kg)
• 1-year OS, NR
• AEs*, 11% (2 mg/kg)
• AEs*, 14% (10 mg/kg)
• ORR, 5.9
• Median PFS, 2.8 mo.
• 1-year OS, 64.5%
• AEs*, NR
418 pts 268 pts
540 pts 103 pts
Pembrolizumab (Phase 2)
*Grade 3-4; Aes, adverse events; ORR, objective response rate; NR, not reported; OS, overall survival; PFS, progression-free survival
20. Homet Moreno B, Ribas A. British Journal of Cancer. 2015;112(9):1421-7.

20. Systemic therapy options for advanced melanoma (10)
dacarbazine
Cytotoxic & Biochemotherapy
Paclitaxel
Temolozomide/cisplatin/vinblastine
Albumin-bound
Carboplatin/
temolozomide
+ IL-2/Interferon 
Dacarbazine/cisplatin/vinblastine
WT (based on status, 1st/2nd-line/best supportive care) BRAFV600 (based on status, 1st/2nd-line*/best supportive care)
Pembrolizumab
NivolumabImatinib for tumors
with activating C-KIT
mutations
Biochemotherapy
Iplimumab High-dose IL-2
Cytotoxic agents
Pembrolizumab
Nivolumab
Imatinib for tumors
with activating C-KIT
mutations
Iplimumab High-dose IL-2
Cytotoxic agents
*If not used first-line, consider vemurafenib/trametinib for selected patients/dabrafenib + trametinib/biochemotherapy for selected patients.
Overall evaluation: reassess disease status and treat according to appropriate pathway.
10. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Melanoma. Version 3.2015 http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf.

21. Systemic therapy options for advanced lung cancer (12-13)
Small-cell lung cancer (SCLC)
Adenocarcinoma, large cell, NSCLCa Squamous, NSCLCa
Nivolumab
Pemetrexed
Erlotinib*/
Best supportive care
Docetaxel Gemcitabine
Ramucirumab +
docetaxelErlotinib
Nivolumab
Gemcitabine
Docetaxel Erlotinib
Ramicurimab + docetaxel
Erlotinib*/
best supportive care
Continuation/switch
maintenance:
Gemcitabine/erlotinib/
docetaxel/
Close observation
aon/after progression on platinum-based chemotherapy; *Provide agent to erlotinib-naïve patients
Overall: Follow respective treatment pathways tailored for response/stable disease/ progression.
12. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-Small-Cell Lung Cancer. Version 7.2015 . http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
13. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Small-Cell Lung Cancer. Version 1.2016 2015. http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.
Ongoing studies
of immune
blockade in SCLC
pts
Combined SCLC & NSCLC as well as low, intermediate & high-grade
neuroendocrine tumors should be treated according to NCCN guidelines
for neuroendocrine tumors & NSCLC.

22. Anti-PD1 agents hold promise in treatment of advanced lung
cancer (21-23)
 Nivolumab, 272 pts
 ORR, 20%
 Median OS, 9.2 mo.
 1-year OS, 42%
 AEs, 7%*
 Pembrolizumab (2 or 10 mg/kg), 495 pts
 ORR, 19.4%
 Median OS, 12 mo.
 Median PFS, 3.7 mo.
 AEs, acceptable
NSCLC (WILD-TYPE, SQUAMOUS), PHASE 3 (2)
*Grade 3-4; AEs, adverse event; (vs. 55% in docetaxel control group) ORR, objective response rate; NR, nost reported; OS, overall survival; PFS, progression-free survival
21. Rothschild SI. Cancers. 2015;7(2):930-49.
22. Brahmer J, Reckamp KL, Baas P, et al.. New England Journal of Medicine. 2015;373(2):123-35.
23. Garon EB, Rizvi NA, et al. New England Journal of Medicine. 2015;372(21):2018-28.
NSCLC (WILD-TYPE), PHASE 1b (3)
SELECTED NSCLC MOLECULAR SUBTYPES (1)
EGFR ALK ROS1
BRAF
KRAS
c-MET RET
PIK3CA
FGFR1
DDR1
Preclinical Undergoing clinical evaluation Most effectively targeted oncogenes in NSCLC

23. Future directions

24. Continued screening of lung cancer in high-risk candidates (11)
 Age 55-74 y and
 ≥30 pack-year history of smoking and
 Smoking cessation <15 years
OR
 Age ≥50 years and
 And ≥20 pack-year history of smoking and
one additional risk factor (other than
second-hand smoke)
11. NCCN Practice Guidelines in Oncology. Lung cancer screening. http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf.
Smoking/
cancer
history
Radon
exposure
Occupatio
nal
exposure
Smoking
exposure
Signs of
lung
cancer
Family history
of lung cancer
in 1st-degree
relatives
Disease history
(pulmonary lung
fibrosis/COPD)

25. Earlier detection of cutaneous melanoma in high-risk
candidates* (10,24)
*Summary of best practices from regional guidelines
10. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Melanoma. http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf.
24. Watts C, Dieng M, Morton R, et al. British Journal of Dermatology. 2015;172(1):33-47.
+ History of prior
melanoma
+ History of prior
melanoma
+Actinic/solar lentigines
+ History of prior
melanoma
+Blond/red hair, light eye color
+History of intense intermittent
sun exposure
RISK FACTORS SOME SCREENING
MANAGEMENT SUGGESTIONS
• Regional-guideline-
recommended risk factor
assessment
• Dermoscopy for pigmented
skin lesions
• For pts. at risk of 1◦ disease,
add total body photography
• Periodic/annual surveillance
of high risk pts.

26. New BRAFi/MEKi combination therapies for melanoma (25)
CR, complete response; n.r., not reported; OR, objective response rate; MDoR, median duration of response;
mPFS, median progression-free survival; mOS, median overall survival
25. Ascierto PA, Marincola FM, et al. J Transl Med. 2015;13(1):213.

27. Novel “non-immune” targets revealed via in silico
prescription (26)
PIK3CA driver mutation in 9 cancer types i.e., breast carcinoma, lung squamous cell carcinoma, uterine
corpus endometrioid carcinoma, lower grade glioma, stomach adenocarcinoma, colorectal
adenocarcinoma plus in 3 more and in the PAN-cancer analysis
Breast carcinoma driver gene cloud
Pancreatic adenocarcinoma, acute lymphocytic leukemia, small cell lung
cancer
Cutaneous melanoma, prostate cancer
Stomach adenocarcinoma, thyroid cancer, pylocytic astrocytoma
Renal clear cell carcinoma, colorectal adenocarcinoma, acute myeloid
leukemia
459 Cancer Driver Genes in 28 Tumor Types
Lung adenocarcinoma, medulloblastoma tumors, esophageal cancer
Glioblastoma multiforme, chronic lymphocytic leukemia, hepatocarcinoma
Breast cancer, serious ovarian adenocarcinoma, neuroblastoma, uterine
corpus endometroid carcinoma, bladder cancer, multiple myeloma
Lung squamous cell carcinoma, low-grade glioma, diffuse B-cell lymphoma
Head-and-neck squamous cell carcinoma, non-small cell lung cancer
26. Rubio-Perez C, Tamborero D, et al. Cancer Cell. 2015;27(3):382-96, blog: http://bg.upf.edu/blog/2015/03/new-intogen-web-to-explore-driver-genes-across-cancer-types/#more-3771

28. Selected companies in the ACT space (27)
*other cancers; ACT, adoptive cell transfer; GPC-3, glypican 3, a hepatocellular carcinoma immunomarker;
WT-1, Wilms Tumor Protein
27. June CH, Riddell SR, Schumacher TN. Sci Transl Med. 2015;7(280):280ps7.

29. Genetic manipulation of NK-cells can potentially improve
cancer outcomes (28)
aNKRs, activating NK cell receptors; iNKRs, inhibitory NK cell receptors; 28. Carlsten M, Childs RW. Frontiers in Immunology. 2015;6:266.
Persistence
• Autocrine
cytokine
stimulation
Migration
• Introduction
of
chemokine
receptors
and
adhesion
molecules
Cytotoxicity
• Introduction of
CARs/aNKRs
• Silencing of iNKRs
• Autocrine cytokine
stimulation
• Protection from
suppressor cytokines
NK
NK
NK
Tumor cell

30. Examples of NK Cell Modalities to Gene Manipulate for
Improved Clinical Efficacy (28)
28. Carlsten M, Childs RW. Frontiers in Immunology. 2015;6:266
29. Coppola A, Arriga R, et al. NK Frontiers in Medicine. 2015;2:33.
Persistence/Expansion Migration Cytotoxicity
Autocrine cytokine production
(IL-2, IL-15, and mbIL-15)
CCR7 and CXCR3 CARs, CD16, autocrine
cytokine production (IL-2 and
IL-15), and overexpression of
double negative TGF-β II
receptor to avoid suppressive
effects of TGF-β. Silencing of
inhibitory NK cell receptors,
such as NKG2A
NK cells have proven anti-tumor activity in preclinical models and myeloid leukemia, in part because of
their cytotoxic functions and abilities to shape a proinflammatory tumor microenvironment. The role of
NK cells in the clinical course of solid tumors is a subject of ongoing investigation (29).