Detailed description of use of immunotherapy in oncology and its mechanism of action

1. Cancer Immunotherapy
Student : Dr Rajesh Patidar
Moderator : Prof. Dr K C Lakshmaiah

2. What is the Immune System?
A biological collection of organs, specific cells,
molecules, and other components that protect body
against foreign matter1
Immune cells and the substances they make travel
through the body to protect it from infectious
pathogens and can also help protect against cancer cell
proliferation2
1. Abbas et al, 2011; 2. Widmaier et al, 2006

3. BasisforAntimicrobialResponse
 Immune system can distinguish self from non-self and
vigorously attack non-self and infected self tissues1
 Utilizes numerous mechanisms to fight disease
 Phagocytosis
 Antimicrobial peptides
 The complement system
 Adapt to and recognize specific pathogens
1. Harris et al, 2013

4. Immune Subsystems
 The human immune system can be classified into two different
subsystems
 Innate immunity (or non-specific immune system), which reacts
rapidly to any foreign substance
 Adaptive immunity (or specific immune system), which
provides a somewhat slower reaction to specific foreign
substances

5. Cells of the Immune System
Innate Immunity
(rapid response)
Adaptive Immunity
(slow response)
Macrophage Dendritic
cell
Mast cell
γδ T-cell
NKT cell
NK cell
Basophil
Complement
protein
Eosinophil
Granulocytes
Neutrophil
B cell
Antibodies
T-cell
CD4+ cell CD8+ cell

6. Innate Immunity
 The innate immune system includes inherited physical and
biochemical structures present from birth that protect the body
from invading substances Innate immune defenses are non-
specific
 Respond to pathogens in a generic way
 This system does not confer long-lasting immunity against a
pathogen1
 The innate immune system is the dominant system of host
defense in most organisms2
1. Alberts et al, 2002; 2. Litman et al, 2005

7. Innate Immunity
 Innate immunity includes two layers of protection
 External (primary) defenses
 Internal (secondary) defenses The body’s internal defenses
activate the internal system by triggering the body’s
inflammatory response

8. Inflammatory Response
 The inflammatory response activates other components of the
innate immune system’s internal defenses
 Phagocytes
 Natural killer (NK) cells
 Antimicrobial proteins
 Cytokines (e.g., histamine, prostaglandins, etc.)
 Kinins
 Chemical reactions initiated by the complement system

9. Complement System
 The complement system
 A group of 20+ proteins
 Stimulates other immune system elements
 Can also cause lysis of bacteria and certain other cells
 Interferons and proteins are the two main types of non-
specific antimicrobial proteins

10. ADAPTIVE IMMUNITY
 Also called specific or acquired immunity
 Develops upon exposure to a pathogen or foreign substance
 Creates immunological memory
 Substances causing this response are antigens
 The immune response can destroy anything containing the
antigen, whether bacteria or cancer cells
 Adaptive immunity is highly specific to its molecular structural
characteristics
 This leads to an enhanced immune response to subsequent
encounters with that same pathogen1
1. Abbas et al, 2011

11. Adaptive Immunity
 The process of adaptive or acquired immunity is the basis of
vaccines
 By exposing the immune system to an inactivated form of a
pathogen, vaccination protects the person from ever
contracting the disease

12. Lymphocytes
 Lymphocytes are involved in adaptive immunity
 There are various classes of lymphocytes
 B lymphocytes recognize soluble antigens and develop into
antibody-secreting cells
 Helper T lymphocytes recognize antigens on the surfaces of
antigen-presenting cells(APCs) and secrete cytokines
 Cytokines stimulate different mechanisms of immunity and
inflammation

13. Lymphocytes
 Cytotoxic T lymphocytes recognize antigens on infected cells and
kill these cells
 Regulatory T cells suppress and prevent immune response (e.g.,
to self antigens)
 NK cells use receptors with more limited diversity than T or B cell
antigen receptors

14. Types of Specific Immune Response
Humoral Immunity
 Mediated by proteins,
including antibodies, in the
blood and other bodily
fluids
 Produces a cascade of
chemicals from the
complement system
 Antibodies are produced by
plasma cells (derived from
B cells)
 Bind to specific antigens,
inactivating them and/or
marking them for
destruction
Cellular Immunity
 Also called cell-mediated
immunity
 Mediated by T cells
 May attack target cells
directly or indirectly by
activating other immune cells
 Enhances the inflammatory
response
 Cellular immunity primarily
targets antigenic molecules
and microorganisms

15. Immune System Disorders
 Immunodeficiency may be due to an immune system that is less
active than normal
 Recurring and life-threatening infections
 Result of genetic conditions, acquired disease(HIV), or the use of
immunosuppressive medication1
 Autoimmunity
 Results from a hyperactive immune system
 Attacks body’s innate tissue as a foreign pathogen
 Common autoimmune diseases include Hashimoto's thyroiditis,
rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus
erythematosus

16. What is immunotherapy?
• The NCI defines immunotherapy as “treatment to boost or
restore the ability of the immune system to fight cancer,
infections, and other diseases”1
• Tumor immunotherapy aims to
 augment the weak host immune response (active
immunity)
administer tumor-specific antibodies or T cells, a form of
passive immunity2
1. National Cancer Institute, 2014; 2. Abbas et al, 2011

17. How Does it Work?
• Immunotherapy does not work in one specific mechanism of
action
• However, all immunotherapy modalities are intended to
augment or restore the body’s own immune function by some
means1
• May be quite different from the traditional cancer treatments
of chemotherapy/targeted therapy, radiation, and surgery,
which intend to act directly upon the targeted tumor
1. Mellman et al, 2011

18. Treatment Approaches
• In immunotherapy, each modality may encompass several
different treatment approaches alone or combination of:
– Therapeutic cancer vaccines
– Cytokines
– Immunological checkpoint inhibitors
– Targeted monoclonal antibodies

19. T-cell Activation and Tumor Suppression
• Antigen-presenting cells (APCs) take up foreign antigens, are
processed by the APC and then bound to major
histocompatibility complex (MHC) molecules on the APC
surface
• MHC molecules present the processed antigen to T cells
• T cells interact with the complex formed by antigen bound to
MHC molecule, producing a T-cell activation signal known as
signal 11
1. Bowes et al, 2014

20. T-cell Activation and Tumor Suppression
• Complete activation requires a second APC signal, known as
signal 2
• Once activated, T cells can directly kill tumor cells that express
the antigen for which it has specificity
• Activated T cells can release cytokines that kill tumor cells or
chemicals that attract other immune cells (e.g.,
macrophages), to destroy tumor cells1
1. Bowes et al, 2014

21. Immuno-Oncology: an emerging immunotherapy
strategy for treating cancer
Therapeutic
vaccines
Enhancing
immune
cell function
Adoptive
Antitumour
mAbs
Bavituximab Adoptive
cell transfer
Modulate T cell
function
Cytokines
GSK1572932A
TG4010
Belagenpumatucel-L
Tergenpumatucel-L
Racotumomab
L-BLP25
CIMAvax
Passive (adoptive)
Designed to act at tumour;
immune-based mechanism
Active
Designed to act on the immune system itself
Immunotherapy
Antigen dependent
Antigen
independent
Immuno-Oncology
CTLA-4 inhibition
PD-1 inhibition
PD-L1 inhibition

22. Three main approaches of cancer
immunothearpy
1.nonspeciific stimulation of immmune reactions
• Stimulate effactor cells IL2(melanoma and renal cancer)
• Inhibit regulatory factor
– Anti CTLA4 (melanoma)
– AntiPD-1(Mealnoma ,lung cancer)

23. 2. Active immunization to enhance antitumor reaction
(cancer vaccine)
2. Passively transfer activated immune cells with antitumor activity
(adoptive immunotherapy)

24. Non SPECIFIC APPROACHS TO CANCER
IMMUNOTHERAPY
• Mechanism of action
 Activate quiescent tumor reactive immune cells.eg IL2
 Remove inhibitory mechanism from immunsuppressed cell to
function to their full capacity.eg CTLA4 inhibitor, anti- PD-1

25. INTERLEUKIN -2
• In 1976 Morgan et al showed that a factor from stimulated
human blood lymphocyte can allow ex vivo growth and
expansion of T lymphocyte .
• This factor(soluble T-cell growth factor=IL2) further allowed
the ability to culture T cells in vitro.
• In 1983 cDNA clone for IL2 isolated.
• In 1984 recombinant IL2 produced which permitted mass
manufacturing

26. INTERLEUKIN -2
• In 1985 Rosenberg SA et al did a study in which IL2 was given
with non specific lymphokinin activated natural killer cell and
found regression of cancer (melanoma,renal, lung and colon)
• Follow up trial by same found that response was due to IL2
not by LAK.

27. INDICATIONS AND USAGE
• adults with metastatic renal cell carcinoma (metastatic RCC).
• adults with metastatic melanoma.
• Careful patient selection is mandatory prior to the administration of
Proleukin.
• Therapy with Proleukin should be restricted to patients with normal
cardiac and pulmonary functions as defined by thallium stress testing
and formal pulmonary function testing.
• caution should be used in patients with a normal thallium stress test
and a normal pulmonary function test who have a history of cardiac
or pulmonary disease.

28. INDICATIONS AND USAGE
• adults with metastatic renal cell carcinoma (metastatic RCC).
• adults with metastatic melanoma.
• Careful patient selection is mandatory prior to the administration of
Proleukin.
• Therapy with Proleukin should be restricted to patients with normal
cardiac and pulmonary functions as defined by thallium stress testing
and formal pulmonary function testing.
• caution should be used in patients with a normal thallium stress test
and a normal pulmonary function test who have a history of cardiac
or pulmonary disease.

29. Retreatment with Proleukin is contraindicated in
patients who have experienced
• Sustained ventricular tachycardia (≥5 beats)
• Cardiac arrhythmias not controlled or unresponsive to management
• Chest pain with ECG changes, consistent with angina or myocardial
infarction
• Cardiac tamponade
• Intubation for >72 hours
• Renal failure requiring dialysis >72 hours
• Coma or toxic psychosis lasting >48 hours
• Repetitive or difficult to control seizures
• Bowel ischemia/perforation
• GI bleeding requiring surgery

30. Checkpoint Modulators

31. Checkpoint (Inhibitory) Molecules
• Numerous inhibitory “checkpoint” molecules and signaling
pathways exist
• Contribute to maintenance of immune balance
– Prevent unwanted autoimmunity and damage to normal
tissues by modulating the duration and scale of the immune
response
• Key checkpoint molecules include:
– Cytotoxic T-lymphocyte antigen-4 (CTLA-4)
– Programmed death 1 (PD-1) receptor
– Lymphocyte activation gene-3 (LAG-3)
• Identified as targets for active immunotherapeutic approaches
to cancer
Pardoll. Nat Rev Cancer. 2012;12:252–264.

32. Adapted from Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
Targeting CTLA-4 and PD-1 pathways
with monoclonal antibodies
T cell Tumour cell
TCR
PD-L1
PD-1
T cell
Dendritic
cell
MHC
TCR
CD28
B7 CTLA-4
- - -
Activation
(cytokines, lysis, proliferation,
migration to tumour)
B7
+++
+++
CTLA-4 pathway
(Blockade with anti-CTLA-4 MAb)
PD-1 pathway
(Blockade with Anti PD-1 MAb)
Anti-CTLA-4
Anti-PD-1/PD-L1
Lymph nodes Tumour microenvironment
+++
PD-L2
PD-1
Anti-PD-1
- - -
- - -
MHC

33. The CTLA-4 Checkpoint Signaling Pathway
• CTLA-4 is expressed on activated T cells to regulate the duration and
amplitude of T-cell activation by counteracting the activity of the
costimulatory molecule, CD28
• When CTLA-4 binds to B7 ligands, T-cell activation is inhibited
• Interaction maintains immune system balance and prevents
unwanted autoimmunity
T-cell
in-activation
APC
CTLA-4
T-cell
Anti-CTLA-4
MAb
APC
T-cell
activation
T-cell
resting
T-cell
APC
T-cell
activation
CD28
B7
TCR
HLA

34. Anti–Cytotoxic T Lymphocyte Antigen 4
• CTLA-4 is an immunosuppressive costimulatory receptor found
on newly activated T cells (and on regulatory T cells)
• It binds with costimulatory ligands B7-1 and B7-2 on antigen-
presenting cells.
• When CTLA-4 is engaged by B7-1 or B7-2, the T cells becomes
inhibited.
• So it suggests that CTLA-4 likely evolved as a self-protective
mechanism to prevent autoimmunity
• overcoming this checkpoint molecule was an aim of cancer
immunotherapy.

35. • In phase III randomized trial comparing dacarbazine plus ipilimumab
versus dacarbazine showed improved survival in that arm containing
ipilumumab (11.2 months versus 9.1 months; p <0.001).
• These studies showing survival benefit led to FDA approval of
ipilimumab for advanced melanoma in 2011.

36. • Ipilimumab was also tested on other solid tumors, and renal
cell cancer appears to be the only other type beside melanoma
that had significant responses.
• Sixty-one patients with metastatic renal cell cancer were
treated, and six developed a response (10%);however, 33%
developed grade 3/4 IRAEs.
• The availability of agents with lower toxicity profiles such as
sunitinib and sorafenib prevented further enthusiasm to
pursue this drug for renal cell cancer.

37. • Recommended Dosing
The recommended dose of Ipilimumab is 3 mg/kg administered
intravenously over 90 minutes every 3 weeks for a total of four
doses.

38. Recommended Dose Modifications
• Withhold scheduled dose of Ipilimumab for any moderate
immune-mediated adverse reactions or for symptomatic
endocrinopathy.
• Permanently discontinue Ipilimumab for any of the following:
1) Persistent moderate adverse reactions or failure to complete
full treatment course within 16 weeks from administration of
first dose

39. 2)Severe or life-threatening adverse reactions, including any of the
following: ƒ
a)Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in
stool frequency (7 or more over baseline), stool incontinence, need for
intravenous hydration for more than 24 hours, gastrointestinal
hemorrhage, and gastrointestinal perforation ƒ
b)Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5
times the upper limit of normal or total bilirubin >3 times the upper limit
of normal ƒ
c)Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic, bullous, or
hemorrhagic manifestations
ƒd)Severe motor or sensory neuropathy, Guillain-Barré syndrome, or
myasthenia gravis ƒ

40. • e)Severe immune-mediated reactions involving any organ
system (eg, nephritis, pneumonitis, pancreatitis, non-
infectious myocarditis) ƒ
• Immune-mediated ocular disease that is unresponsive to
topical immunosuppressive therapy
• Another anti–CTLA-4 antibody, tremelimumab (previously
called CP-675,206), has also demonstrated durable responses
in melanoma patients

41. Anti–Programmed Death 1 and
Anti–Programmed Death Ligand 1

42. The PD-1 Checkpoint Signaling Pathway
• PD-1 is an immunomodulatory receptor that belongs also to
the CD28-B7 Ig superfamily
• Two known ligands: PD-L1 and PD-L2
• Main role is to limit the activity of T cells in peripheral tissues,
maintaining
self-tolerance and preventing unwanted autoimmune damage
Pardoll. Nat Rev Cancer. 2012;12:252–264.

43. MHC
PD-L1
PD-1 PD-1
PD-1
PD-1
Anti-PD-1 MAb blocks the PD-1 receptor
Recognition of tumour by T cell through MHC/antigen
interaction mediates IFNγ release and PD-L1/2 up-
regulation on tumour
Priming and activation of T cells through MHC/antigen
& CD28/B7 interactions with antigen-presenting cells
T cell
receptor
T cell
receptor
PD-L1
PD-L2
PD-L2
MHC
CD28 B7
T cell
NFκB
Other
PI3K
Dendritic
cell
Tumour
cell
IFNγ
IFNγR
Shp-2
Shp-2
Adapted from Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
Anti-PD-1: mechanism of action

44. • PD-1 is another checkpoint modulator expressed on activated
T cells.
• Interaction with its corresponding ligand, PD-L1 (B7-H1) and
PD-L2 (B7-H2) leads to suppressed T effector function.
• PD-1 is expressed on hematopoietic and epithelial cells and is
upregulated by cytokines such as IFNγ
• PD-L1 is mainly on antigen-presenting cells.

45. Nivolumab
• Nivolumab (previously known as BMS-936558, MDX-1106,
and ONO-4538) is a fully human anti–PD-1 IgG4 monoclonal
antibody
• It is indicated for the treatment of patients with melanoma
 unresectable disease
 metastatic melanoma
 disease progression following ipilimumab.

46. Nivolumab in lung cancer
• FDA approved nivolumab for patients with metastatic
squamous NSCLC with progression on or after platinum-based
chemotherapy on March 4, 2015.
• On October 9, 2015, FDA approved nivolumab for the
treatment of patients with metastatic non-squamous NSCLC
 with progression on or after platinum-based chemotherapy
 Patients with EGFR or ALK genomic tumor aberrations should
have disease progression on FDA-approved therapy for these
aberrations prior to receiving nivolumab

47. • Patients stratified by prior use of maintenance therapy and line of treatment
(second vs third-line)
• ORR and PFS secondary endpoints assessed by investigator
– Tumor response assessment (RECIST v1.1) performed at week 9 and every 6
weeks thereafter until PD, discontinuation of study therapy, lost to follow-up,
withdrawal of consent, or start of subsequent anti-cancer therapy
• Minimum follow-up was 13.2 months
• Results based on a 18 March 2015 database lock
CA209-057 (CheckMate 057) - Study Design
Endpoints
Primary
• OS
Secondary
• ORR
• PFS
• Efficacy by PD-L1 expression
• Disease-related symptom
improvement rate by week 12
Nivolumab
3 mg/kg IV q2w,
until PD, unacceptable
toxicity, or other
protocol-defined reasons
Docetaxel
75 mg/m2 IV q3w,
until PD, unacceptable
toxicity, or other
protocol-defined reasons
Randomize
1:1
•Stage IIIB/IV non-squamous NSCLC
•1 prior platinum-doublet based
chemotherapy
•Prior maintenance therapy with
pemetrexed, bevacizumab, or
erlotinib allowed
•Prior ALK inhibitor allowed for
known ALK translocation or EGFR
mutation
•ECOG PS 0–1

48. 12-mo OSa 18-mo OSb
Nivo (n = 292) Doc (n = 290) Nivo (n = 292) Doc (n= 290)
mOS, mos 12.2 9.4 12.2 9.4
1-yr OS rate, % 51 39 51 39
18-mo OS rate, % – – 39 23
No. of events/Total no.
of patients, n/N
190/292 223/290 206/292 236/290
HR (96% CI) = 0.73 (0.59, 0.89)
P = 0.0015
HR (95% CI) = 0.72 (0.60, 0.88)
Post-hoc P = 0.0009c
aBased on a March 18, 2015, DBL. bBased on a July 2, 2015, DBL. cThe formal primary end point testing was based on the interim analysis (March 18, 2015).
For full description of the additional follow-up data, an updated p-value is provided based on the July 2, 2015, DBL.
Symbols represent censored observations.
Overall Survival
100
90
80
70
60
50
40
30
10
0
20
27
18
15
9
6 21
12
3
0 24 30
Nivolumab
Docetaxel
No. of patients at risk (18-mo OS)b
292 233 195 171 148 128 107 55 4
27
290 244 194 150 111 89 61 23 4
0
0
6
Nivolumab
Docetaxel
18-mo OS rate = 23%
18-mo OS rate = 39%
1-yr OS rate = 39%
1-yr OS rate = 51%
Time (mos)
OS
(%)
Nivolumab
Docetaxel
No. of patients at risk (12-mo OS)a
292 232 194 169 146 123 62 32 0
9
290 244 194 150 111 88 34 10 0
5
0
0
• Minimum follow-up for 12-mo OS rate, 13.2 mos; for 18-mo OS rate, 17.1 mos
49

49. Nivolumab in renal cell cancer
• FDA approved nivolumab in advanced renal cell carcinoma in
patients who has received prior antiangiogenic therapy on 23
novmber 2015
• The recommended dose of nivolumab is 3 mg/kg
administered as an intravenous infusion over 60 minutes
every 2 weeks until disease progression or unacceptable
toxicity.

50. Withhold Nivolumab for any of the following:
 if patients develops pneumonitis or colitis
 Aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) greater than 3 times ULN or total bilirubin greater than 3
times ULN
 Any other severe or Grade 3 treatment-related adverse
reactions

51. • Pembrolizumab is also a PD1 inhibitor which got accelerated
approval for treatment of NSCLC in metastatic setting which
progressed on paltinum based chemotherapy or targeted
therapy
• Atezolizumab (MPDL3280A) a new anti–PDL1 in clinical trials
has also shown some efficacy in melanoma, renal cell cancer,
and NSCLC in early reports

52. Adoptive Cell Transfer Immunotherapy

54. • Transfer of the tumor-bearing host of immune lymphocytes with
anticancer activity.
• The first successful administration of adoptive cell therapy (ACT)
involving TIL, in combination with high-dose IL-2 was carried out at
the National Cancer Institute in 1988
• Studies that used cell transfer therapy in patients with metastatic
melanoma have provided the clearest evidence of the power of the
immune system to mediate the regression of advanced metastatic
cancers in humans.
• Lymphocytes with antitumor activity can be expanded to
very large numbers ex vivo for infusion into cancer patients.

55. • In patients with metastatic melanoma, TILs can be obtained from
resected tumor deposits
• These cells are then expanded ex vivo and reinfused along with IL-2
• IL2 is the requisite growth factor required for the survival and
persistence of these cells
• Preparative lymphodepleting chemotherapy regimen, consisting of
cyclophosphamide and fludarabine with or without 2 or 12 Gy total
body irradiation, substantially enhances the survival and
persistence of the transferred cells and increase their in vivo
antitumor effectiveness

56. • In a series of three pilot trials with 93 patients, objective responses
were seen in 49% to 72% of patients .
• Of the 93 patients, 20 (22%) experienced a complete regression of all
metastatic melanoma. Only 1 of these 20 patients has recurred, and
the remaining patients have on going complete regressions from 80
to over 104 months . The 5-year survival of these 93 patients was
29% and was similar regardless of the prior treatments that these
patients had received.

57. • Genetic Modification of Lymphocytes for Use
in Adoptive Cell Therapy: Basic Principles and
Applications to Solid Tumors

58. Types of Gene Transfer to T Cells
• The difficulty in obtaining TILs with antitumor activity from cancers
other than melanoma has also led to the development of
genetically modified lymphocytes.
TCR Gene Therapy
• The first step in TCR gene therapy is to isolate a T-cell clone with
high affinity for a defined target antigen.
• Genes encoding the TCR can be isolated from patients with rare
reactive high avidity T-cell clones that recognize and lyse target
tumor cells.

59. Types of Gene Transfer to T Cells
• The TCR α and β chains are identified, isolated and cloned into either
retroviral or lentiviral vectors using recombinant DNA techniques.
• The genetic transfer of TCR α and β chains directed against specific tumor
antigens can create generic antigen-specific T-cells.
• The first successful transfer of a melanoma-reactive TCR to human
peripheral blood lymphocytes (PBLs) conferring anti-tumor reactivity was
reported in 1999,
• This approach bypasses the need to isolate the tumor-specific effector
cells from each patient.

60. first human clinical trial of TCR gene
• The first human clinical trial of TCR gene therapy was reported in 2006
for the treatment of metastatic melanoma.
• In this phase I trial, HLA-A2-positive metastatic melanoma patients were
treated with retrovirally-transduced autologous PBLs expressing a TCR
against MART-1.
• Gene transfer efficiency in this trial was in the range of 21–72% as
assessed by the staining for the TCR beta chain, and was distributed
equally between CD4 and CD8 cells.
• Gene-modified T cells were detected as long as 1 year after adoptive cell
transfer. Following T cell infusion, tumor regression was observed in 2 out
of 17 patients.
• In addition to the initial report, a total of 31 patients were treated in this
protocol and 4 patients (13%) experienced an objective regression of
metastatic melanoma.
• Response rate in this first human TCR clinical trial is less than that of the
TIL trials that are reported to be in the range of 50–70%.

61. • Instead of transducing T cells with additional αβTCR, it is possible to
transfer chimeric TCRs.
• These consist of
 exodomain an antigen bindiing site
 endodomain T cell signaling pathway
• CARs are generated by joining the light and heavy chain variable
regions of a monoclonal antibody expressed as a single chain Fv
(scFv) molecule with the transmembrane and cytoplasmic signaling
endodomains derived from the CD3 ζ chain of the native T cell
receptor.
• CARs therefore usually combine the antigen specificity of an
antibody and the cytotoxic properties of a T cell in a single fusion
molecule

63. Anti-CD19 Chimeric Antigen Receptors
• The first clinical trial to demonstrate in vivo activity of anti-CD19
CAR T cells in human was conducted using the gammaretroviral
vector encoded a CAR with a CD28 costimulatory domain.
• Patients received cyclophosphamide and fludarabine
chemotherapy followed by an infusion of anti-CD19 CAR T cells and
a short course of intravenous IL-2.
• Clear antigen-specific activity of the anti-CD19 CAR T cells was
demonstrated because blood B cells were selectively eliminated
from four of the seven evaluable patients for several months. The
duration of B-cell depletion in these patients was much longer than
the duration of B-cell depletion caused by the chemotherapy that
the patients received.
• This study also generated evidence of an antimalignancy effect by
the anti-CD19 CAR T cells because six of seven evaluable patients
with advanced B-cell malignancies obtained either complete
remissions or partial remissions

64. Active Immunization Approaches to Cancer
Therapy (Cancer Vaccines)
• The molecular characterization of multiple cancer antigens led
to a large number of clinical trials that attempted to actively
immunize against these antigen.
• The results of these efforts have yet to produce significant
vaccine efforts of value in the treatment of human cancer.
• A variety of immunizing vectors have been used, including
tumor-derived peptides, proteins, whole tumor cells,
recombinant viruses, dendritic cells, and heat-shock proteins
• many of these approaches can lead to the development of
circulating T cells that can recognize the immunizing tumor
antigen, these T cells rarely cause the inhibition of established
tumors,
• Often, T cells with weak avidity for tumor are produced

65. • A prospective randomized trial of immunization with antigen-presenting
cells was carried out by the Dendreon Corporation (Seattle, Washington).
• This trial used an antigen-presenting cell vaccine loaded with prostatic acid
phosphatase linked to GM-CSF compared to placebo in men with
hormone-refractory prostate cancer.
• Out of 331 patients who received the vaccine treatment, only 8 patients
experienced a PSA drop of at least 50%.
• There was no difference in the time to disease progression; however, the
vaccine group had a median survival of 25.8 months compared to 21.7
months in the placebo group, and based on this statistically significant
survival improvement, this treatment was approved by the FDA .