1. 이근욱 분당서울대학교병원/서울의대 혈액종양내과 부교수
제12회 분당서울대학교병원 내과 연수강좌
면역증강 표적항암제란?
이근욱
분당서울대학교병원/서울의대
혈액종양내과 부교수

2. Immunotherapy of cancer
ACTIVE
Acts directly on immune system
PASSIVE (Adoptive)
Targets the tumor; may utilize immune system
Enhancing
immune cell function
Therapeutic
vaccines
Immune checkpoint inhibitors
Cytokines
Inhibition of CTLA-4
PD-1
PDL-1
Anti-tumor
mAbs
Adoptive
Cetuximab
Rituximab
Bevacizumab …
Adoptive cell transfer

3. 19 patients (7%) remain disease-free
RR 20%, including 23 [9%] CR
19 patients (7%) remain disease-free
2 patients with treatment-related mortality
Overall Survival
Klapper JA et al. Cancer 2008

4. MAGRIT a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 as adjuvant therapy in resected MAGE-A3-positive NSCLC
Melanoma-associated antigen 3 (MAGE-A3) is a protein that in humans is encoded by the MAGEA3 gene.
The normal function of MAGE-A3 in healthy cells is unknown.[4] The presence of the antigen on tumor cells has been associated with worse prognosis. In one study, high levels of MAGE-A3 in lung adenocarcinoma were associated with shorter survival.[5]
MAGE-A3 is a tumor-specific protein, and has been identified on many tumors including melanoma, non-small cell lung cancer, hematologic malignancies, among others
Vansteenkiste et al. ESMO 2014

5. TOGA : Trastuzumab for GC (Phase 3)
HER2 overexpression in GC
1:1
Bang YJ et al, Lancet 2010 5

6. Monoclonal Antibodies
Murine Mab
: - omab
Chimeric Mab
: - ximab
Humanized Mab
: - zumab
Basic antibody structure and the different types of therapeutic antibody. (a) Basic antibody structure. (b) Basic structure of a murine, chimeric, humanised, and human monoclonal antibody. Red indicates murine sequence and black indicates human sequence. CDR, complementarity-determining region
Murine monoclonal antibodies (suffix -omab)
Initially, murine antibodies were obtained by hybridoma technology, for which Kohler and Milstein received a Nobel prize. However the dissimilarity between murine and human immune systems led to the clinical failure of these antibodies, except in some specific circumstances. Major problems associated with murine antibodies included reduced stimulation of cytotoxicity and the formation complexes after repeated administration, which resulted in mild allergic reactions and sometimes anaphylactic shock.[8]
[edit] Chimeric and humanized monoclonal antibodies (suffixes -ximab, -zumab respectively)
To reduce murine antibody immunogenicity, murine molecules were engineered to remove immunogenic content and to increase their immunologic efficiency.[8] This was initially achieved by the production of chimeric and humanized antibodies. Chimeric antibodies are composed of murine variable regions fused onto human constant regions. Human gene sequences, taken from the kappa light chain and the IgG1 heavy chain, results in antibodies that are approximately 65% human. This reduces immunogenicity, and thus increases serum half-life.
Humanised antibodies are produced by grafting murine hypervariable[disambiguation needed ] amino acid domains into human antibodies. This results in a molecule of approximately 95% human origin. However it has been shown in several studies that humanised antibodies bind antigen much more weakly than the parent murine monoclonal antibody, with reported decreases in affinity of up to several hundredfold.[10][11] Increases in antibody-antigen binding strength have been achieved by introducing mutations into the complementarity determining regions (CDR),[12] using techniques such as chain-shuffling, randomization of complementarity determining regions and generation of antibody libraries with mutations within the variable regions by error-prone PCR, E. coli mutator strains, and site-specific mutagenesis.[1]
[edit] Human monoclonal antibodies (suffix -umab)
Human monoclonal antibodies are produced using transgenic mice or phage display libraries. Human monoclonal antibodies are produced by transferring human immunoglobulin genes into the murine genome, after which the transgenic mouse is vaccinated against the desired antigen, leading to the production of monoclonal antibodies.,[9] allowing the transformation of murine antibodies in vitro into fully human antibodies.[3]
The heavy and light chains of human IgG proteins are expressed in structural polymorphic (allotypic) forms. Human IgG allotype has been considered as one of the many factors that can contribute to immunogenecity.[13] The general scheme of a monoclonal antibody development program is described in.[14]
[edit] Targeted conditions
Human Mab
: - umab
CDR, complementarity-determining region

10. Immune checkpoints
Co-stimulatory pathways. Co-stimulations either enhance or down-regulate T cell activation following the initial TCR and peptide-MHC ligation. Positive co-stimulatory pathways include B7–CD28, CD40L–CD40, ICOS–ICOS-L, and OX40–OX40L. Negative co-stimulatory pathways include B7–CTLA-4 and PD-1–PD-L.
Immune checkpoints are molecules in the immune system that either turn up a signal (co-stimulatory molecules) or turn down a signal. Many cancers protect themselves from the immune system by inhibiting the T cell signal.
Since around 2010[citation needed] inhibitory checkpoint molecules have been increasingly considered as new targets for cancer immunotherapies due to the effectiveness of two checkpoint inhibitor drugs that were initially indicated for advanced melanoma - Yervoy, from Bristol-Myers Squibb, and Keytruda, from Merck.

11. CTLA vs. PD-1 Ribas A et al. N Engl J Med 2012
CTLA-4 antibodies release an immune checkpoint at the activation step of an immune response to cancer
PD-1 and PD-L1 antibodies release an immune checkpoint at the effector step of n immune response to cancer.
Ribas A et al. N Engl J Med 2012

12. Blockade of CTLA Ribas A et al. N Engl J Med 2015
CTLA-4 antibodies release an immune checkpoint at the activation step of an immune response to cancer
PD-1 and PD-L1 antibodies release an immune checkpoint at the effector step of n immune response to cancer.
Ribas A et al. N Engl J Med 2015

13. Improved survival of melanoma with ipilimumab
626 patients with previously treated melanoma
CTLA-4 antibodies release an immune checkpoint at the activation step of an immune response to cancer
PD-1 and PD-L1 antibodies release an immune checkpoint at the effector step of n immune response to cancer.
Hodi et al. N Engl J Med 2010

14. Pooled survival analysis from all phase I-III, including BMS EAP
CTLA-4 antibodies release an immune checkpoint at the activation step of an immune response to cancer
PD-1 and PD-L1 antibodies release an immune checkpoint at the effector step of n immune response to cancer.

15. Blockade of PD-1 pathway
Ribas A et al. N Engl J Med 2015

16. PD1/PD-L1 inhibitors in clinical development
Target
Agent (Sponsor)
Type of mAb
PD-1
Nivolumab (BMS-ONO; OPDIVO)
IgG4 fully human
Pembrolizumab (MK-3475; Merck Sharp & Dohme; KEYTRUDA)
IgG4 humanized
Pidilizumab (CureTech-Teva)
IgG1 humanized
AMP-514 (AZ/MedImmune)
IgG
PDL-1
Atezolizumab (Genetech/Roche)
IgG1; fully human engineered
Durvalumab (MED4736; AZ/MedImmune)
Avelumab (MSB C; Merck Serno)
IgG1; fully human
BMS (BMS-ONO)
IgG4; fully human
Antibody-dependent cell-mediated cytotoxicity (ADCC)

17. Previously untreated melanoma without BRAF mutation: Nivolumab vs
Previously untreated melanoma without BRAF mutation: Nivolumab vs. Dacarbacine OS
Robert C et al. N Engl J Med 2015

18. Pembrolizumab versus ipilimumab in advanced melanoma
Statistically significant improvement in overall survival with
KEYTRUDA® (pembrolizumab) 10 mg/kg Q3W vs ipilimumab
(hazard ratio [HR]=0.69; 95% confidence interval [CI], 0.52–0.90;
P=0.004) and with KEYTRUDA 10 mg/kg Q2W vs ipilimumab
(HR=0.63; 95% CI, 0.47–0.83; P<0.001).
Robert C et al. N Engl J Med 2015

19. Blockade of PD-1 pathway in other tumors
Alley et al. AACR2015

20. Phase 3 trials of nivolumab in NSCLC

21. Phase 3 trials of nivolumab in NSCLC
Primary endpoint: Overall survival (OS)
CheckMate 017
Squamous NSCLC1
CheckMate 057
Non-squamous NSCLC2
1Reckamp K et al., WCLC 2015; 2Horn L et al., ESMO 2015

22. Phase 3 trials of nivolumab in NSCLC
CheckMate 017
Squamous NSCLC1
CheckMate 057
Non-squamous NSCLC2
1Reckamp K et al., WCLC 2015; 2Horn L et al., ESMO 2015

23. Immune related adverse events (AEs) may be associate with PD-1/PD-L1 blockade
Confirmed immune-related AEs
Flu like febrile sense
Autoimmune hepatitis, elevated transaminases
Colitis / Duodenitis
Rash
Myositis/myasthenia gravis
Pneumonitis
Hypothyroidism / Hyperthyroidism
Pan hypopituitarism (endocrinopathy)
Pancreatitis
Type 1 diabetes mellitus

24. Incidence of Immune-related AEs
( ; Benjamin A. Teply & Evan J. Lipson)

25. Safety Profile of Nivolumab in Patients with Advanced Melanoma
: A Pooled Analysis
Weber JS et al., ASCO 2015 Abstract 9018

26. Pneumonitis
( ; Benjamin A. Teply & Evan J. Lipson)

27. General Management Algorithm of IrAEs

28. Issues & future directions
Cost
Biomarkers predictive of treatment response
Combination of immune checkpoint inhibitors (or with other chemotherapeutic agents)

30. OS with pembrolizumab in NSCLC by PD-L1 expression
Garon et al. N Engl J Med 2015