2. Introduction
ā¢ The term cancer refers to a disease of cells
that show uncontrolled proliferation,
dedifferentiation(anaplasia), invasiveness and
the ability to metastasise (spread to distal
parts of body).
ā¢ Traditional therapies for cancer targets the
tumour and include ā Surgery, radiation,
chemotherapy and targeted therapy.
3. Cancer Statistics in India
ā¢ Estimated number of people living with the disease:
around 2.25 million
ā¢ Every year, new cancer patients registered: Over
11,57,294 lakh
ā¢ Cancer-related deaths: 7,84,821
ā¢ Risk of developing cancer before the age of 75 years
-Male: 9.81%
-Female: 9.42%
ā¢ Cancers of oral cavity and lungs account for over 25%
of cancer deaths in males and cancer of breast and
oral cavity account for 25% cancers in females.
4. Immunotherapy for cancer
ā¢ Immunotherapy represents conceptually a
unique way of dealing with cancer which is to
focus on eliminating cancer indirectly by
harnessing the power of the hostās immune
system.
ā¢ The 2018 Nobel Prize in Physiology or
Medicine has been awarded jointly to two
cancer immunotherapy researchers, James P.
Allison, and Dr. Tasuku Honjo.
5. ā¢ Allison and Honjo were honored for their work on
uncovering ways to activate the immune system
to attack cancer, a breakthrough in developing
new cancer treatments.
ā¢ The discoveries of Honjo and Allison led to the
development of several drugs which allow for the
routine use of effective immunotherapy.
ā¢ Allison studied the T cell protein CTLA-4 and
Honjo discovered PD-1, which is another protein
found on the surface of some T cells. .
6. Mechanisms of cancer immune
evasion
ā¢ downregulation of antigen processing and
presentation machinery and thus antigen
presentation
ā¢ upregulation of PD-L1 on tumor cells and PD-1 on
effector T cells and facilitation of binding of PD-L1
and B7-1/2 to PD-1 and CTLA-4, respectively
ā¢ secretion of immune suppressive modulators
(TGF-Ī², IL-8, IL-10, IL-18, CSF1, VEGF, gangliosides,
ROS, Kynurenines, K+) and metabolites
(adenosine, PGE, lactate) into TME
7. ā¢ deprivation of immune activating metabolites
(glucose, arginine, glutamine, tryptophan)
from TME
ā¢ recruitment and/or activation of immune
suppressive cell populations e.g. Treg, myeloid
derived suppressor cells (MDSC), and tumor-
associated macrophages (TAM)
ā¢ inhibition of effector T cell inļ¬ltration
8.
9. Immunotherapeutic Approaches
ā¢ Immune checkpoint inhibition
ā¢ Vaccination
ā¢ Nonspecific stimulation of T cells
ā¢ Adoptive T Cell Transfer
ā¢ Bispecific Antibodies
10. Immune Checkpoint Inhibitors
ā¢ Inhibitors of Cytotoxic T Lymphocyteā
Associated Protein 4 (CTLA4)
ā¢ Inhibitors of Programmed Cell Death 1 (PD-1)
ā¢ Antagonists of PD-1 Ligand 1
ā¢ Combination of AntiāPD-1 and AntiāCTLA4
13. Inhibitors of Cytotoxic T Lymphocyteā
Associated Protein 4 (CTLA4)
ļ±blocks the interaction of CTLA-4 with B7 ligands
on APCs and thereby augments T-cell activation.
ļ±Ipilimumab
ā¢ Approved in 2011 for Unresectable metastatic
melanoma
ā¢ Approved in 2015 for Adjuvant therapy with
Stage III melanoma
ā¢ Approved in 2017 for Pediatric melanoma
ļ±Tremelimumab
14. Inhibitors of Programmed Cell Death 1
(PD-1)
ļ± blocks the interaction between PD-1 and its ligands.
ļ±Nivolumab
ā¢ Approved in 2014 for Unresectable or metastatic
melanoma with progression after ipilimumab therapy
ā¢ Approved in 2015 for NSCLC with progression after or
on platinum therapy & Metastatic RCC after prior anti-
angiogenic therapy
ā¢ Approved in 2016 for Hodgkin lymphoma & Head and
neck squamous cell carcinoma
ā¢ Approved in 2017 for Urothelial carcinoma, metastatic
colorectal cancer & Hepato cellular carcinoma
15. ļ±Pembrolizumab
ā¢ Approved in 2014 for Advanced or unresectable
melanoma
ā¢ Approved in 2015 for Metastatic NSCLC with PDL-
1 expression and progression on or after
platinum therapy
ā¢ Approved in 2016 for Recurrent SCCHN
ā¢ Approved in 2017 for Hodgkin lymphoma,
Urothelial carcinoma, Gastric & gastroesophageal
carcinoma
16. Antagonists of PD-1 Ligand 1
ļ± blocks the interaction of PD-L1 with PD-1
ļ± Atezolimumab
ā¢ Approved in 2015 for NSCLC with progression after or on
platinum therapy
ā¢ Approved in 2016 for Urolthelial carcinoma with
progression on or after platinum therapy
ļ± Durvalumab
ā¢ Approved in 2017 for Urothelial carcinoma
ā¢ Approved in 2018 for Nonāsmall cell lung cancer
ļ± Avelumab
ā¢ Approved in 2017 for Urothelial carcinoma & Merkel cell
carcinoma
17. Combination of AntiāCTLA4 and Antiā
PD-1
ļ±Ipilimumab + nivolumab
ā¢ Approved in 2015 for Melanoma
ā¢ Approved in 2018 for Renal cell carcinoma
18. Therapeutic cancer vaccines
ā¢ vaccination with a known antigen (to generate
T cells that recognize cells expressing the
antigen)
ā¢ Sipuleucel-T
ā¢ T-Vec
19. Sipuleucel-T
ā¢ In 2010, the FDA approved the first-in-class
cancer treatment vaccine, sipuleucel-T
(ProvengeĀ®, manufactured by Dendreon),
ā¢ for treatment of hormone-refractory prostate
cancer and metastatic prostate cancer.
ā¢ It is designed to trigger an immune response to
prostatic acid phosphatase (PAP), an over-
expressed tumor antigen.
ā¢ Provenge is generated by isolating APCs and
cultured with a PAP linked to GM-CSF.
20.
21. T-Vec
ā¢ T-VEC (talimogene laherparepvec) was approved
by the FDA in 2015 for the local treatment of
unresectable cutaneous and nodal lesions in
patients with melanoma.
ā¢ T-VEC is an oncolytic herpesvirus that replicates
within tumors and expresses GM-CSF.
ā¢ Tumor antigens are released after virally induced
cell death, and the presence of GM-CSF can
promote an antitumor immune response.
22. ā¢ In T-VEC, the HSV-1 genome has been modified by
deletions of 2 copies of the RL1 gene, which encode a
neurovirulence factor, infected cell protein 34.5
(ICP34.5).
ā¢ In healthy cells, ICP34.5 is required for viral
proliferation. In cancer cells, however, HSV-1
proliferation does not require ICP34.5.
ā¢ Thus, deletion of ICP34.5 prevents viral proliferation
within healthy cells, but renders cancer cells
susceptible.
ā¢ This deletion of ICP34.5 makes the virus less
pathogenic, limiting HSV infection of noncancerous
cells, and providing for tumor-selective replication.
23. Inside a healthy cell, the virus
( ) is unable to replicate,
leaving the cell unharmed.
Inside a cancer cell, the virus
replicates and secretes GM-CSF
( ) until the cells lyses,
releasing more viruses, GM-CSF
and antigens ( ).
GM-CSF attracts dendritic cells to the
site, which process and present the
antigens to T cells. The T cells are
now āprogrammedā to identify and
destroy cancer cells throughout the
body.
T cells destroy
cancer cells
throughout the
body, including
those not directly
injected with the
virus.
Talimogene Laherparepvec: Proposed Mechanism of
Action for Systemic Immunologic Effect
24. Nonspecific stimulation of T cells
ļ±Interleukin 2 (as recombinant IL-2, aldesleukin)
ā¢ Interleukin 2 stimulates the proliferation of
activated T cells and the secretion of cytokines
from NK cells and monocytes. IL-2 stimulation
increases cytotoxic killing by T cells and NK cells.
ā¢ Aldesleukin is approved for use in patients with
metastatic renal cell cancer and metastatic
melanoma.
25. Adoptive T Cell Transfer
ā¢ Tumor-Inļ¬ltrating Lymphocytes (TILs)
ā¢ TCR-Transduced T Cells
ā¢ Chimeric Antigen Receptor T Cells (CAR T
Cells)
26.
27. Tumor-Inļ¬ltrating Lymphocytes (TILs)
ā¢ Before the recent development of checkpoint
modulators (anti-PD-1), which shows a
comparable level of response, TILs had been the
only agent approved by the US FDA for patients
with metastatic melanoma.
ā¢ discovered to be mononuclear lymphocytes that
had a propensity to surround and invade tumors.
ā¢ These TILs were ļ¬rst discovered in resected
melanomas and were found to contain a mixture
of both CD4 and CD8 T cells.
28. TCR-Transduced T Cells
ā¢ TCR-transduced T cells are often generated via
genetic induction of tumor-speciļ¬c TCR. This is
often done by cloning the particular antigen-
speciļ¬c TCR into a retroviral backbone.
ā¢ TCR-transduced T cells present many advantages
and solutions to other immunotherapies. Most
importantly, there is a robust ability for TCR-
transduced T cells to be generated against a
plethora of tumor antigens.
31. ļ±Tisagenlecleucel
ā¢ Approved in 2017 for the treatment of children
and young adults with leukemia
ā¢ Approved in 2018 for adults with certain types of
non-Hodgkin lymphoma- specifically DLBCL, high-
grade B-cell lymphoma, and DLBCL that arises
from follicular lymphoma
ļ±Axicabtagene ciloleucel
ā¢ Approved in 2017 for the treatment of diffuse
large B-cell lymphoma(DLBCL)
32. ā¢ CARs contain the antigen-binding domain of a
monoclonal antibody to confer recognition of the
targeted tumor antigen coupled to intracellular
domains capable of activating T cells.
ā¢ When expressed in T cells, these CARs recognize cell
surface antigens and activate T cells independent of
antigen presentation by a MHC molecule as required
for physiologic antigen presentation.
ā¢ CAR targeting CD19, a B-cell antigen, resulted in
striking efficacy in patients with B-cell leukemias.
ā¢ Other CARs targeting CD22 and B-cell maturation
antigen (BCMA) have shown efficacy and are currently
under investigation.
33. Bispeciļ¬c Antibodies to Engage T Cells
ļ±Blinatumomab
ā¢ Approved in 2018 for the treatment of adult and
pediatric patients with B-cell precursor acute
lymphoblastic leukemia(ALL)
ā¢ The beneļ¬ts of bispeciļ¬c antibodies (bsAbs) rely
on their ability to target 2 unique cell types and
direct immune eļ¬ectors towards cancer cells.
ā¢ Blinatumomab is a CD3/CD19 bispeciļ¬c antibody
that act by targeting the TCR on T cells (CD3) and
recruiting them to B cells (CD19).