immunotherapeutic approaches in cancer, immune checkpoint inhibitors, cancer vaccines, sipuleucel T, chimeric antigen receptor T cells, bispecific antibodies

1. Immunotherapeutic Approaches
In Cancer
By- Dr. Rahul Kumar Bhati

2. Introduction
• 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).
• Traditional therapies for cancer targets the
tumour and include – Surgery, radiation,
chemotherapy and targeted therapy.

3. Cancer Statistics in India
• Estimated number of people living with the disease:
around 2.25 million
• Every year, new cancer patients registered: Over
11,57,294 lakh
• Cancer-related deaths: 7,84,821
• Risk of developing cancer before the age of 75 years
-Male: 9.81%
-Female: 9.42%
• 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
• Immunotherapy represents conceptually a
unique way of dealing with cancer which is to
focus on eliminating cancer indirectly by
harnessing the power of the host’s immune
system.
• 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. • 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.
• The discoveries of Honjo and Allison led to the
development of several drugs which allow for the
routine use of effective immunotherapy.
• 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
• downregulation of antigen processing and
presentation machinery and thus antigen
presentation
• 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
• secretion of immune suppressive modulators
(TGF-β, IL-8, IL-10, IL-18, CSF1, VEGF, gangliosides,
ROS, Kynurenines, K+) and metabolites
(adenosine, PGE, lactate) into TME

7. • deprivation of immune activating metabolites
(glucose, arginine, glutamine, tryptophan)
from TME
• recruitment and/or activation of immune
suppressive cell populations e.g. Treg, myeloid
derived suppressor cells (MDSC), and tumor-
associated macrophages (TAM)
• inhibition of effector T cell infiltration

9. Immunotherapeutic Approaches
• Immune checkpoint inhibition
• Vaccination
• Nonspecific stimulation of T cells
• Adoptive T Cell Transfer
• Bispecific Antibodies

10. Immune Checkpoint Inhibitors
• Inhibitors of Cytotoxic T Lymphocyte–
Associated Protein 4 (CTLA4)
• Inhibitors of Programmed Cell Death 1 (PD-1)
• Antagonists of PD-1 Ligand 1
• Combination of Anti–PD-1 and Anti–CTLA4

11. Immune checkpoints- inhibitory
signals that limit T-cell activation

12. Fundamental Mechanisms of Immune
Checkpoint Blockade Therapy

13. Inhibitors of Cytotoxic T Lymphocyte–
Associated Protein 4 (CTLA4)
blocks the interaction of CTLA-4 with B7 ligands
on APCs and thereby augments T-cell activation.
Ipilimumab
• Approved in 2011 for Unresectable metastatic
melanoma
• Approved in 2015 for Adjuvant therapy with
Stage III melanoma
• Approved in 2017 for Pediatric melanoma
Tremelimumab

14. Inhibitors of Programmed Cell Death 1
(PD-1)
 blocks the interaction between PD-1 and its ligands.
Nivolumab
• Approved in 2014 for Unresectable or metastatic
melanoma with progression after ipilimumab therapy
• Approved in 2015 for NSCLC with progression after or
on platinum therapy & Metastatic RCC after prior anti-
angiogenic therapy
• Approved in 2016 for Hodgkin lymphoma & Head and
neck squamous cell carcinoma
• Approved in 2017 for Urothelial carcinoma, metastatic
colorectal cancer & Hepato cellular carcinoma

15. Pembrolizumab
• Approved in 2014 for Advanced or unresectable
melanoma
• Approved in 2015 for Metastatic NSCLC with PDL-
1 expression and progression on or after
platinum therapy
• Approved in 2016 for Recurrent SCCHN
• Approved in 2017 for Hodgkin lymphoma,
Urothelial carcinoma, Gastric & gastroesophageal
carcinoma

16. Antagonists of PD-1 Ligand 1
 blocks the interaction of PD-L1 with PD-1
 Atezolimumab
• Approved in 2015 for NSCLC with progression after or on
platinum therapy
• Approved in 2016 for Urolthelial carcinoma with
progression on or after platinum therapy
 Durvalumab
• Approved in 2017 for Urothelial carcinoma
• Approved in 2018 for Non–small cell lung cancer
 Avelumab
• Approved in 2017 for Urothelial carcinoma & Merkel cell
carcinoma

17. Combination of Anti–CTLA4 and Anti–
PD-1
Ipilimumab + nivolumab
• Approved in 2015 for Melanoma
• Approved in 2018 for Renal cell carcinoma

18. Therapeutic cancer vaccines
• vaccination with a known antigen (to generate
T cells that recognize cells expressing the
antigen)
• Sipuleucel-T
• T-Vec

19. Sipuleucel-T
• In 2010, the FDA approved the first-in-class
cancer treatment vaccine, sipuleucel-T
(Provenge®, manufactured by Dendreon),
• for treatment of hormone-refractory prostate
cancer and metastatic prostate cancer.
• It is designed to trigger an immune response to
prostatic acid phosphatase (PAP), an over-
expressed tumor antigen.
• Provenge is generated by isolating APCs and
cultured with a PAP linked to GM-CSF.

21. T-Vec
• 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.
• T-VEC is an oncolytic herpesvirus that replicates
within tumors and expresses GM-CSF.
• Tumor antigens are released after virally induced
cell death, and the presence of GM-CSF can
promote an antitumor immune response.

22. • 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).
• In healthy cells, ICP34.5 is required for viral
proliferation. In cancer cells, however, HSV-1
proliferation does not require ICP34.5.
• Thus, deletion of ICP34.5 prevents viral proliferation
within healthy cells, but renders cancer cells
susceptible.
• 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 “programmed” 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
Interleukin 2 (as recombinant IL-2, aldesleukin)
• 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.
• Aldesleukin is approved for use in patients with
metastatic renal cell cancer and metastatic
melanoma.

25. Adoptive T Cell Transfer
• Tumor-Infiltrating Lymphocytes (TILs)
• TCR-Transduced T Cells
• Chimeric Antigen Receptor T Cells (CAR T
Cells)

27. Tumor-Infiltrating Lymphocytes (TILs)
• 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.
• discovered to be mononuclear lymphocytes that
had a propensity to surround and invade tumors.
• These TILs were first discovered in resected
melanomas and were found to contain a mixture
of both CD4 and CD8 T cells.

28. TCR-Transduced T Cells
• TCR-transduced T cells are often generated via
genetic induction of tumor-specific TCR. This is
often done by cloning the particular antigen-
specific TCR into a retroviral backbone.
• 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.

29. Chimeric Antigen Receptor T Cells
(CAR T Cells)

31. Tisagenlecleucel
• Approved in 2017 for the treatment of children
and young adults with leukemia
• 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
Axicabtagene ciloleucel
• Approved in 2017 for the treatment of diffuse
large B-cell lymphoma(DLBCL)

32. • 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.
• 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.
• CAR targeting CD19, a B-cell antigen, resulted in
striking efficacy in patients with B-cell leukemias.
• Other CARs targeting CD22 and B-cell maturation
antigen (BCMA) have shown efficacy and are currently
under investigation.

33. Bispecific Antibodies to Engage T Cells
Blinatumomab
• Approved in 2018 for the treatment of adult and
pediatric patients with B-cell precursor acute
lymphoblastic leukemia(ALL)
• The benefits of bispecific antibodies (bsAbs) rely
on their ability to target 2 unique cell types and
direct immune effectors towards cancer cells.
• Blinatumomab is a CD3/CD19 bispecific antibody
that act by targeting the TCR on T cells (CD3) and
recruiting them to B cells (CD19).

35. THANK YOU