Therapeutic immunology Flashcards
What are examples of passive immunotherapies?
Rituximab which targets CD20 and it used in lymphomas
Herceptin/Trazatumumab which targets Her2 and used in breast cancer
Gemtuzumab organamicin which targets CD33 and is used in AML
Alemtzumab which targets CD52 and is used in CLL
Bevacizumab which targets VEGF and is used in colon cancer
Cetuximab which targets EGFR and is used in Colon cancer
What is cellular therapy?
The most effective form of immunotherapy currently available for patients with solid tumours is adoptive-cell transfer (ACT)
This process involves the isolation of tumour specific T cells, their activation and expansion to large numbers ex vivo and their subsequent readministration to the patient
The addition of a lymphodepleting preparative regimen and exogenous cytokine support such as IL-2 will improve the antitumour effects of the transferred lymphocytes
How effective is cellular therapy?
About half of the patients with refractory metastatic melanoma respond to ACT therapy, while some nasopharyngeal carcinomas and lymphomas of viral etiology may also be responsive
What are the 2 major hurdles to the wider application of ACT?
An inability to produce lymphocytes that react with common epithelial tumors and the poor in vivo function and persistence of lymphocytes after extensive in vitro culture
How are EBV-specific CTLs?
PBMCs are isolated by centrifugation, most of these are then frozen but a few are infected with EBV resulting in the production of an EBV transformed LCL which will strongly express EBV antigens
The frozen PBMCs are now mixed with irradiated LCLs, some of these PBMCs will be CTLs to EBV antigens, these will become activated an proliferate the culture is stimulated by the further addition of LCLs and IL-2 eventually the non-activated PBMCs will die through a lack of stimulation and only the CTLs which recognize EBV antigends will survive
EBV-CTLs are then induced via a retroviral vector which stably integrates into the cells genome and allows PCR tracking
After various safety checks the EBV-CTLs can be administered back to the patient
What are the advantages of anti B cell antibodies for treatment of conditions such as lymphomas?
They are readily available
What are the disadvantages of anti B cell antibodies for treatment of conditions such as lymphomas?
There is exacerbation of immunodeficiency during profound B cell depletion
May be selection in the cancer for CD20- population
B cell depletion and thus therapeutic effect lasts about 6 months
The concentration which reaches the brain may be below therapeutic level
What are the advantages of adoptive transfer of EBV specific CTLs for treatment of conditions such as lymphomas?
They are specific for EBV infected cells
They are well tolerated when used a prophylaxis or for treatment of non-bulky disease
What are the disadvantages of adoptive transfer of EBV specific CTLs for treatment of conditions such as lymphomas?
Only available in a limited number of centres
Labour intensive therapy to produce
Time is required to generate sufficient cell numbers
Can cause severe side effects in the case of bulky disease inflammation at the tumour site
Escapes of mutant tumor cells
Persistence in presence of immunosupprseeive treatment post SOT unknown
What is the role of EBV in lymphomas?
Both Hodgkin lymphoma, post-transplant lymphomas and non-hodgkins lymphoma can be EBV driven
This creates the potential that EBV antigens may a target for CTLs
However EBNA1 is processed by MHC 1 antigens by tumour cells LMP2 however is consistently expressed on the malignant populations in lymphoma and its eptiopes are conserved throughout viral strains, however LMP2 is not highly immunogenic
How do we bias the CTL response to be EBV to be towards LMP2?
Replace LCLs as APCs for the first stimulation for dendritic cells which have been engineered to express LMP2 from an adenovirus vector
Uses of LCLs which over express LMP2 from the same adenovectorfor subsequent stimulations
This approach expands polyclonal populations of both CD4 and CD8 T lymphocytes which are specific for this weak tumour antigen
After infusion into patients diagnosed with LMP2 positive lymphomas LMP2 reactive T cells increased in number in the circulation and at tumour sites producing sustained tumor responses
What are human tumour associated antigens detected by immune cells?
There are a large number of antigens expressed only in tumours and testis in adults
These antigens are intracellular or surface antigens though some are secreted
Some are specific for the cancer such as immunoglobulin idiotypes in lymphoma and myeloma
These antigens have differencing degrees of immunogeneicity with some such as melanoma antigens causing a strong T lymphocyte response
How can an anti-idiotype vaccine be used in lymphoma?
Each patient with non-Hodgkins B cell lymphoma or myeloma has a unique idiotype for their tumour making it a potential target for tumour specific cellular or antibody therapy
Lymphoma patients may be vaccinated after chemotherapy to stave off tumour reoccurance this generates both an anti-Id humoral response and a cellular response
What correlates to a better outcome for patients with follicular lymphoma?
An anti-idiotype response and FcRIIIa 158 valine/valin genotype
What is Wilms tumour gene?
This codes for the WT1proteins which is overexpressed in leukaemia and various types of solid tumours giving it potential as a pan-tumour associated antigen and target for GVL
This protein is also highly immunogenic so both CTLs and antibodies to this produce are spontaneously induced in patients
