Recent advances in Immunotherapy

1. BY NIDHI MAHESHWARI
RECENT ADVANCES IN
IMMUNOTHERAPY

2. Definitions
Immunopharmacology: Study of drugs
altering immune system.
Immunomodulators: These are the drugs
which alters the immune system to
suppress it (immunosuppressants ) or
enhance it (immunostimulants).

3. Why Immunomodulators?
Immunosuppressants for treatment of :
Transplant rejections
Autoimmune diseases
Inflammatory conditions
Immunostimulants for treatment of:
Cancer
Infectious diseases

4. Immunosupressants
• Inhibitors of lymphocyte gene expression to reduce inflammatory
response: Glucocorticoids
• Inhibitors of lymphocyte signaling to prevent immune cell
activation and proliferation
1) Calcineurin inhibitors
Cyclophillin binding drugs: cyclosporine, ISA (TX-247)
FKBP-12 binding drugs: Tacrolimus, modified release
Tacrolimus
2) mTOR inhibitors: Sirolimus, Everolimus
• Cytotoxic agents to reduce lymphocyte proliferation:
antimetabolites, alkylating agents
1) Inhibitors of purine synthesis: mycophenolate mofetil,
enteric coated mycophenolic acid, mizoribine
2) Inhibitors of pyrimidine synthesis: Leflunomide, FK 778
• Cytokine Inhibitors: TNF-α, IL-1,IL-2 antagonists

5. • Antibodies against specific immune cell molecule:
polyclonal and monoclonal antibodies
• Inhibitors of immune cell adhesion and activation:
Efalizumab, Alefacept
• Allergan Immunotherapy
• Tolerogens or inhibitors of immune cell costimulation:
Anti-CD80, Anti-CD86, Abatacept, Belatacept
• Rho (D)Immune globulins
• Helminthic therapies
• Sphingosine1 phosphate receptor modulator: Fingolimod

6. ISATX-247
 Semisynthetic analogue of cyclosporine
 More potent, less nephrotoxic
 Less glucose intolerance
 In phase II clinical trial
Modified release tacrolimus
 once a day, better compliance than BD tacrolimus
Enteric coated mycophenolate
 Introduced for better upper GI tolerability than
mycophenolate.
Mizoribine
 Introduced in japan
 Better tolerability than azathioprine
 Used in renal transplantation, steroid resistant nephrotic
syndrome, lupus

7. FK778
 Leflunomide synthetic derivative
 similar therapeutic efficacy
 extended T1/2 side effect of leflunomide is reduced
Rilonacept
 IL-1 antagonists
 Used in US for familial cold autoinflammatory syndrome
 Was in phase III trial for gout, not approved for same in US in 2012
Allergan Immunotherapy
 Modify the natural course of allergies-reduce sensitivity to allergans
 Useful for allergic rhinitis or asthma
 Desensitization
 Eg: Grazax-(sublingually) grass pollen extracts

8. Tolerogens

9. To induce T cell anergy or tolerance
Use operative co-suppressive pair to dampen
immune response
CTLA-4 on T cells with CD80 and CD86 on
Antigen Presenting Cells
Less opportunistic infections or secondary tumors
No drug available for clinical use till now
Potential tolerogens in renal transplantation are:
Humanised anti-CD 80 Mab and Humanised anti-
CD 86 Mab

10. Abatacept
1st
generation CTLA4-Ig fusion protein,
binds to CD 80/86 on APC and inhibits T
cell costimulation
Recently approved for resistant cases of
RA
Undergoing trials in patients of organ
transplantation
Belatacept
Newer CTLA4-Ig fusion protein
Higher affinity for CD 80/86
For kidney transplantation

11. Helminthic therapy
Whipworm ova and hookworm used
Highly effective in relapsing-remitting multiple
sclerosis (RR-MS), crohn’s disease, allergies and
asthma
Several proposed mechanisms are:
1. Re-polarisation of the Th1 / Th2 response: down
regulate Th1. IL-12, IFN-γ, TNF –ά, promoting
production of regulatory Th2 cytokines IL-10, IL-4,
IL-5, IL-13

12. Sphingosine -1-phosphate receptor modulator:
FINGOLIMOD
Reduces recirculation of lymphocytes from the
lymphatic system to the blood & peripheral tissue
Reversibly & specifically sequesters host
lymphocytes into the lymph nodes
In phase III for RR-MS and Kidney
transplantation

13. Immunostimulators
Cell based (Dendritic) therapy
Antibody based therapy
Cytokine based therapy
T cell adoptive transfer
Autologous immune enhancement therapy
Genetically engineered T cells
Immune recovery
Check point antibodies

14. Cell based therapy (cancer vaccines)
Immune cells specific for the tumor will
be activated, grown and returned to the
person with cancer where the immune
cells provoke an immune response against
the cancer
Eg: Sipuleucel-T (Provenge) for prostate
cancer

15. A complete sipuleucel-T treatment repeats three courses, with two weeks
between successive courses

16. Antibody based therapy
Antibodies specific to cancer antigens are used
Eg: EGFR, HER2
Cell death by ADCC, activating the complement
system, prevent a receptor interacting with
its ligand or deliver chemotherapy or radiation,
all of which can lead to cell death.
Eg: Alemtuzumab, Bevacizumab Cetuximab

17. Cytokine based therapy
Eg: IL-2, IF-alpha
Enhance immune system, has antitumor activity
 Interferon-α is used in the treatment of hairy-cell
leukaemia, AIDS- related Kaposi's sarcoma, follicular
lymphoma, ,chronic myeloid leukaemia and malignant
melanoma
Interleukin-2 is used in the treatment of malignant
melanoma and renal cell carcinoma

18. T-cell adoptive transfer
• Passive immunization
• T cells transfused
• Removed from a) Tumor infiltrating lymphocytes (TILs) b)
blood
• Ex vivo activation and expansion is done by
a) gene therapy (Genetically engineered T cells)
b) exposing to tumor antigens
• No approved T cell therapy as such

19. Autologous immune enhancement
therapy
• Patient's own peripheral blood-derived NK
cells, Cytotoxic T Lymphocytes and other
relevant immune cells are expanded in vitro and
then reinfused
• Mostly for CANCER
• There are also studies proving their efficacy
against Hepatitis C Viral infection,Chronic
fatigue Syndrome and HHV6 infection.

20. Immune recovery
Cytokines
IL-7: for cancer and HIV patients
IL-2 : for HIV patients

21. Immune check point
blockade
In normal physiology
PD=Programmed cell death 1
In cancer: there is up-regulation of PDL1 on cancer cells
May inibit T cells which destroy cancer cells
Antibodies that bind to either PD-1 or PD-L1 and therefore block the
interaction may allow the T-cells to attack the tumor

22. Eg: Nivolumab
Block PD-1, on the surface of activated T
cells
In clinical trials
For treatment of cancer

23. Check point antibodies
Directed against cytotoxic T-lymphocyte antigen
4 (CTLA-4) and programmed death 1 receptor
(PD-1)
CTLA-4 attenuates the early activation of naïve
and memory T cells.
CTLA4, a protein receptor down regulates the
immune system
PD-1 is primarily involved in modulating T cell
activity in peripheral tissues via interaction
with its ligands, PD-L1 and PD-L2

24. Ipilimumab
•CTLA4 inhibitor: down regulates CTLA4 and increase immune
system
•For metastatic melanoma, approved by USFDA in 2011
•Tried alone and with dacarbazine in phase III trials-high
survival rate was shown
•Undergoing trials for non small cell lung cancer, small cell
lung cancer, bladder and prostate cancer
•Adverse effects: stomach pain, constipation, bloating
•Very very costly
• By Bristol Squibbs
• Available in New Delhi

25. Vemurafenib
•BRAF kinase inhibitor
•V600Emutated BRAF inhibition.
•BRAF V600 mutation positive unresectable/metastatic
melanoma, the most aggressive form of skin cancer.
•Approved by USFDA in 2011
•40% cases show resistance in some time of treatment
•Side effects: skin lesions, arthralgia, photosensitivity

26. Tremelimumab
• Metastatic pancreatic cancer
• A fully human mab binding to CTLA4 on T
cells
• Stimulates the immune system by blocking
the CTLA4-negative regulatory signal
• Phase Ib trial
• Evaluating the safety, tolerability, and
maximum tolerated dose (MTD) of
tremelimumab combined with gemcitabine in
patients with metastatic pancreatic cancer.

27. References
 Sharma & Sharma
 Tripathi
 Katzung
 Wikipedia
 Ann Oncol (2014) 25 (9): 1750-1755.doi: 10.1093/annonc/mdu205
 Ann Oncol (2012) 23 (suppl 8):viii15-viii21.doi: 10.1093/annonc/mds258