LMP299Y1 Lecture Notes - Chimeric Antigen Receptor, Tumor Microenvironment, Pd-L1

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3 Jun 2013
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LMP April 3
Cancer a lot of commonality
Most cancers develop as response to cytotoxic stress so for example, gastrointestinal cancers, lung
cancers or even homological cancers tend to develop at sites of inflammation crhonic smoking leads to
chronic inflammation in the lungs, killing many cells, and cells activate primordial ddefense mechanisms,
behaving like bacteria and unicellular organisms to try and survive, activate pathways that lead to
genetic instability selection for cell population that can continually grow despite conditions in the
microenvironment that tells them to not to get this behaviour
Hallmarks of cancer
Degenerates into disease with different cellular organisms but similar hallmarks cancer cells develop
insensitivity to that encourage own blood supply can grow indefinitely
For a cell to grow indefinitely glycolysis fatty acid oxidation all hallmarks of cancer
Hallmarks are immunosuppressant and resistant to T cell makes sense because immune system is
designed to kill/limit situations that endanger the organism and so the immune system should be able to
kill cancer cells in order for cancer to develop must develop mechanisms to resist T cells
Why might T clel immunotherapy be effective treatment modality the first justification is that cancer
cells are not normal cells in order to evolve, expresses new genes, mutated genes gene expression
patterns that differ from normal cells recognize altered molecular patterns cancer cells recognizable
by cells of immune system antigens that can stimulate T cells in general, represent altered proteins
or protein expression levels that from classic immunology proteins degraded in the proteasome
peptides bound to MHC molecules T cells through receptors activated, kill them cancer antigens
include products of mutated genes (p53 ex can get mutated if disabled or mutated so no longer
functional, tumour cells do not die when should not) products of rearranged genes - chromosomal
aberrations are major hallmark of cancer genes can get juxtaposed, recombined, class rearrangement
of leukemia brc-chromosome 10 result in fusion protein that is a kinase that never gets constitutively
active kinase can drive leukemia cells to grow but this is novel protein adjoining region has never
been seen before by immune system as much an antigen as viral antigen that comes in during
infection BCR can get broken down and presented on MHC to serve as T cell targets a lot of cancers
lose differentiation state, acquire fetal characteristics, fetal genes would not necessarily be encountered
by immune systems, so when expressed, become targets for T cells
Gp100 and trp2 involved in normal function of melanocytes get overexpressed higher levels than
should be they can now get recognized by T cels because amount of binding to MHC is such that
immune system cannot recognize it
Immune system arose to deal with viral infections but principal same for cancer
Viral antigens processed and presented by APC come back to site of viral infection bind to targets
with appropriate antigens, get activated T cells activated locally and kill the virally infected cells
tumour immunology prinicpals are the same T cells can recognize targets on tumour cells can come
into tumour microenvironment eliminate antigen expressing tumour cells like eliminate viral
expressing cells
T cell mediated immunotherapy can be effective strategy for cancer treatment one of the few types of
treatments for cancer that actually is curative is bone marrow transplantation procedure offered to
patients with certain types of leukemia leukemia are cancers of the bone marrow could be treated
by high doses of cytotoxic chemotherapeutic drugs if did not give intense therapy, did not kill of all the
tumour cells tumors relapsed kill more leukemia cells, potentially get rid of all of them kill off all
normal hemoatostemic cells (die of plastic anema, not able to make red cells, neutrophils, platelets)
Easy to grow hematopoetic stem cell system by putting bone marrow into patient, reconstitute patient
replace diseased bone marrow with bone marrow from normal patient procedure pioneered in sixties
and seventies give patient high doses of chemotherapy come in with bone marrow from atched
donor, could eliminate leukemia but got graft-vers-host disease this procedure transferred T cells from
donor into patient along with hematopoetic stem cells when doing transplant from matched donor,
you collect bone marrow stem cells from bone marrow itself or from the blood infuse into patient
T cells see MHC molecules of patient expressing proteins of patient normal gene products T celsl from
different environment, do not tolerate activated by the antigens in the patient and get systemic
activation of T cells that can cause significant damage to tissues, such as intestine, liver, skin at the
same time T cells can recognize leukemia cells, which are also foreign T cells clear leukemia cells but
ALSO cause systemic GVH disease so the idea was that in patients, mimic GVH and get the therapeutic
effects of the GVH
In bone marrow transplant, induce systemic generalized immunity immunity comes form amount of
genetic mismatch from donor T cells and patient in order for patient to survive procedure the T cells
used have to be such that they don’t recognize too many antigens in the patient, should not be too
many genetic differences and because most of the antigen disparity is transmitted through HLA system
one has to use a donor that is quite closely matched at the HLA loci the best donor would be family
member of sibling
Problem of GVH even if have matched onor can be stressful to body elderly less able to stand
stresses of prolonged inflammation BMT offered to younger patients with sibling donor and the
problem is many patients with cancer are past this age, no longer eligible
AC AD BC BD four siblings if AC has cancer, but the other three are not eligible to donate
High age and low likelihood of elibible matched sibling so low chance
Minor antigens would serve as source of antigen to drive GVH disease so MUD transplants still toxic
because can induce GVH disease
Autotransplants take patients own bone marrow, get rid of leukemia cells, use to reconstitute patients
but NO T CELL immunotherapy tumour progressed because T cells recognized tumour cells so
relapse a big problem
Haploid identical transplants
Vaccines provide T cell therapy to patients
Receptor fused to tumour cell get benefits of adoptive T cell therapy without GVH simplest form of
Graft versus tumour effect
Make chimeric antigen receptor T cells take T cells from patient, grow in lab and infect with construct
that is a variant of antibody that has targeting moiety that can bind to target cell when the T cell
recognizes target, fires off, becomes activated and can kill target chimeric antigen receptor T cells
T cells circulate in patient recognize CD18 variant B cells include tumour cells kill them without
causing toxicity no GVH disease
Works!
Day 21 bone marrow brown are CD19 positive lymphoma cells before procedure, lots of them,
after procedure on day 41, less then 177, normal BM develops
This wipes out normal be cell compartment
Almost all T cells able to re ognize tuour reactive T cells no cure for the most part
50% of patients relapsed despite having taken care of problem of tumour reactive T cells
Cenral problem of immunotherapy is intrinsic resistance of tumour cells to T cells central hallmark of
cancer now most important problem in T cell immunotherapy
Has a number of mechanisms by which it can shut off tumour reactive T cells on an APC and tumour
are all sorts of co-stimulatory molecules that send signals into the T cells to get activated if have T cell
binding to tumour cell, signal 1 is MHC peptide complex then there is signal two and signal three,
costimulatory signals that are required to cooperate with the T cell receptor signal that allow T cell to
proliferate, sustain activation, engage in functional immune response
Molecules for signal 2 CD28 on T cell that binds to CD8, CD6 ox40 and CD70 are other costimulatory
receptor stimate repairs that provide signals that sustain a productive T cell response negative
regulatory signals molecule like PDL1 binds to PD1 on T cell and shuts down response or CTLA4 on T
cell when it binds to CD8 or CD6 on APC or tumour cell also shuts things down so tumour cells have
high level expression of negative regulatory molecules first ones dealt with are PDL1 and CTLA4
logical approach would be to make antibodies against PDL1 or PD1 or against CTLA4 and infuse those
into patient block negative signal, productive T clel responses take place, clear tumour cells
First trials of Abs against PD1
Microenvironment tumour consists of T cell and tumour cells and more tumour microenviroment
seen as player in functional immune response
Microevn has T cells, tumour cells, and supporting cels like B cells, macrophages, fibroblasts, and ideally
what dendritic cells is support an effective T cell response against tumour cells the type of immune
response that one needs to get in microtumour env is TH1 response (where T cells make a lot of IFN
gamma, and this cytokine activates cytotoxic cells, NK cells, CD8 cells, and induces signalling pathways in
cancer cells that make them receptive to killing mechanisms) TH1 response need to be supported by
macrophages that support pro-inflmammatory state’s ability to have a lot fo IFN gamma and tumour
necrosis factor that can lead to killing of tumour clels support function of NK and CD8 cells dendritic
cells have to have appropriate function to support this behaviour all of the cells in the inflammatory
cells in microenvironment need to work together to force type 1 behaviour that llows sustained killing
response
Tumour cells tend to make factors that prevent this all macrophage state, B cell state, neutrophil state,
all are plastic T cells can get classified into Th1 cells, TH2 cells macrophages into M1, M2 cells
immune system can polarize itno two different responses killing responses embodied by TH1 type of
differentiation state IFN gamma, tumour necrosis factor, help kill stressful agents in the body on the
other hand, can polarize to wound-repair situation, TH2 type of differentiation state, where factors like
immunosuppressive molecules like IL10 are made, damps down immune response
These occur for all cells in immune system
Cancer cells and multiple immunosuppressive cell types
Different regulatory cells induced can reinforce each others behaviour regulatory T cells can induce B
ells to amplify regulatory environment
Does not seem likely that single molecule would be able to make significant impact on the system
If one was to look for genetic marker of this immunosuppressive microenvironment the best one is
STAT3 STAT3 is transcription factor that activates a lot of immunosuppressive factors IL10 and IL6
actually also activates anti-apoptotic cells cells tend to be able to survive and grow a lot of