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60. Gene therapy ( 基因治疗)61. Cancer vaccines ( 肿瘤疫苗 )
62. Cell transfer therapy ( 免疫细胞 )
63. Antiangiogenesis agents ( 抗血管生成 )
64. Focused ultrasound
65. Antisense inhibition of gene expres.
DeVitaDeVita Cancer: Cancer: Principles and Practice of OncologyPrinciples and Practice of Oncology
Part IV: Newer Approaches in Cancer TreatmentPart IV: Newer Approaches in Cancer Treatment
(most of them are tumor biotherapy)(most of them are tumor biotherapy)
Most active research area for cancer treatment
Hundreds protocols are in clinic trials
Why tumor Bio-therapy?
Current anti-tumor therapy used in Clinic:
Surgery: primary tumor, No metastases
Radiation : surface, small and localized tumors
Chemotherapy: liquid tumor, metastases
Tumor Bio-therapy
Problems with chemotherapy: • Most drugs target nucleic acid
synthesis or mitosis, affect both tumor
and normal dividing cells, cause side-
effects on patients.
• Tumor cells: genetic instability,
heterogeneous, drug-resistant cells can
survive and grow
• Abnormal vessel structures & high
pressure in tumor resulted in lower
drug concentration in the lesion.
Tumor Bio-therapy
Influence of specific genesAntisense oligo or SiRNA,Gene therapy ( deliver target genes into tumor cells through vector)
Immuno-therapyTumor vaccines, Cytokines, Antibodies,
Anti-Angiogenesis Signal transduction: More active in Cancers
e.g. STI-571 (inhibit Bcr-Abl tyrosine kinase)
Gene Therapy: A Brief HistoryGene Therapy: A Brief History
Jesse Gelsinger ,1999
Ashanti de Silva , 1990
Alain Fischer ,2003
1990 Ashanti de Silva , USA
(ADA 所致联合免疫缺陷)1999 Jesse Gelsinger , USA
2003 Alain Fischer , France
2003 Adrian Thrasher , UK
Gene Therapy• Genetic Disease , single gene related• Present: most in Tumor (Multiple genes)• Method Ex vivo : modify target cell in vitro
In situ : directly introduce into local tumors( most commonly used; p53-AV )In vivo : injected into blood (immune-genes)
Key : target gene; vector; efficiency
Target Genes :1. regulate immune response: cytokine, tumor Ag … etc
2. Differential expressed: TSG, apoptosis, angiogenesis etc.
How to introduce Genes into cells:
1. naked DNA , liposome , receptor …
2. Virus vector: replicate-deficient
(for transfection; no replication in human)
widely used: adenovirus (AV), AAV, Retrovirus
Obstacles in Gene Therapy - Obstacles in Gene Therapy - vectorvector
The major problem is the carrier ( vector ) ,not the Genes
Lack the efficient and specific vector. The most widely used vector is virus vector
(adenovirus 腺病毒载体 ) Major drawback of AV vector is
High immunogenecity andlow specificity for tumors
High immunogenecity of vectorHigh immunogenecity of vector
载体免疫原性强和靶向性差
Immunogenecity of Adenovirus
Adenovirus
Target - specificity
The problem with Gene therapy is mainly due to
vector (immunogenic and low specificity for tumor)
Tumor Bio-therapy
• Influence of specific genesAntisense oligo or SiRNA,Gene therapy
• Immuno-therapyTumor vaccines, Cytokines, Antibodies…
• Angiogenesis ( 抗血管生成 ):block new blood vessel (血管) formation
• Signal transduction: More active in Cancerse.g. STI-571 (inhibit Bcr-Abl tyrosine kinase)
The elimination phase of Cancer Immunoediting
Dunn et al, Nature Immunology, 2002; 3:991Dunn et al, Nature Immunology, 2002; 3:991
Effective immune responses eliminate
tumor
Tumors must escape from immune
recognition
Dunn et al, Nature Immunology, 2002; 3:991Dunn et al, Nature Immunology, 2002; 3:991
Mechanisms with host immune system
Ignorance: Immune system does not recognize t
he low levels of TAA at early phases of tumor
Tolerance of T cells to TAA, resulted from T-cel
l anergy or deletion (caused by host APC, T-reg)
Suppression of T cells: tumor-derived factors, i
mmunosuppressive myeloid cells or T-reg
Defects in antigen presentation by professional a
ntigen-presenting cells
Tumor Vaccine ( treatment, not prevention)Cell based vaccine: Best and most widely used so far
tumor cell based vaccine: hard to get enough cells;
DC ( 树突状细胞) based vaccinewidely used in clinic
Anti-tumor effector arms of the immune response
Tumor vaccines:Use Dendritic cells, the most powerful APC, to elicit anti-tumor immune responses
DC
DC
Tc
Interaction between DC and lymphocytes
DC uptake tumor cells, digest and processed tumor Ag into smaller peptide, form a complex with MHC, and present to the effectors ( 效应细胞 ).
Two Critical factors that affect DC vaccine1. Antigen loading2. Stimulating effective anti-tumor imm
unity (high affinity CD8+ CTL)
Ex vivo loading of DC with tumor Ag
Some Facts about Tumor Antigens
• Complete repertoire of tumor Ags and their
encoding genes is far from being fully
defined.
• The gene profiles from different types of
cancers or even from the same type in
different individuals are significantly
diversified.
• Only a small fraction of genes have been
repeatedly cloned from different cDNA
libraries prepared from distinct, or even the
same type of cancer in different individuals.
• Use a single Tumor antigen to load DC, can easily generate tumor cells that loss this Ag (immune pressure/selection)
• So, whole cells antigens are used in
most studies/clinical trials.
• Include: tumor cell lysates, apoptotic tumor cells, necrotic tumor cells, tumor-DC fusion
Adaptive immune responses can be divided into
two related activities—recognition and response.
require co-operation between Lymphocytes and
Ag presenting cell (APC, 抗原递呈细胞 )
Activation of T cells by dendritic cells
Antigen-presentation alone is NOT sufficient
to trigger immune response
The host immune response is tightly regulated by
1. Inhibitory (抑制 ) signals (e.g for NK cells)
2. Co-stimulatory (共刺激 ) factors (two signals):
without them, Ag presentation resulted in
Anergy (无反应 ) or immuno-tolerance (耐受 )
3. Danger Signals
危险?自己人?抗原
处理抗原摄取抗原
S1
S2
效应细胞APC 免疫应答
APC 双信号
?
Can we use adjuvant ( 佐剂) to activate APC,
(increase the co-stimulatory signals),
during the Ag loading?
Tumor Vaccine: Limited success obtained in clinic, more challenges remain
Other Vaccines:• DNA vaccine• Protein/peptide vaccine (8-12 AA): tumors
may not express peptide (heterogeneity 异质性 )
• Others: virus, xenogeneic ( 异种) vaccine etc
Get more “fighter”?
culture immune cells in vitro (>1010)
Problem:
functional activity? Reach the tumor?
In vivo, only high affinity CD8+ CTL can response to low levels of Tumor Ag, proliferate, and provide protective immunity;
Generation of these CTL dependent on the expression of co-stimulatory molecules on DC
Thus , effective loading of tumor Ag, helping the maturation and expression of co-stimulatory molecules on DC simultaneously ( 同
时) are the dreams of tumor-immunologists.
Cytokines:• Interferon ( 干扰素 ), activate NK cells, M
• IL-2 , IL-12: activate T-cells;• TNF: direct or via M and CTL to kill tumor
These cytokines are Not specific for tumor cellsUsually need high doses; with side-effectsMainly used as assistant therapy
Antibody: several Ab are in clinic use(e.g., for Her-2 in breast cancer)
篦麻毒素
Problems in using Antibody to treat
cancer:
1. Difficulty of Ab to penetrate into
solid tumor
2.Only minority of tumor cells
express the targeted Ag, due to
heterogeneity of tumor cell
population
3. Blocking effect of high circulating
tumor Ag
4. Formation of anti-IgG Ab and
toxicity of immune complexes
Cancer immunotherapy: moving beyond
current vaccinesNATURE MEDICINE 2004 , 10 : 909-915
Great progress has been made in the field of tumor
immunology in the past decade, but .......
In our cancer vaccine trials of 440 patients
(NCI), the objective response rate was low
(2.6%), and comparable to the results
obtained by others.
Promising, Great efforts still needed