BY NIDHI MAHESHWARI

RECENT ADVANCES INIMMUNOTHERAPY

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).

Why Immunomodulators?

Immunosuppressants for treatment of :Transplant rejectionsAutoimmune diseasesInflammatory conditions

Immunostimulants for treatment of:Cancer Infectious diseases

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

Cyclophil l in binding drugs: cyclosporine , ISA (TX-247)

FKBP-12 binding drugs: Tacrol imus, modified release Tacrolimus

2) mTOR inhibitors: Sirolimus, Everolimus• Cytotoxic agents to reduce lymphocyte proliferation:

antimetabolites, alkylating agents 1) Inhibitors of purine synthesis: mycophenolate mofeti l , enteric coated mycophenolic acid, mizoribine 2) Inhibitors of pyrimidine synthesis: Leflunomide, FK 778• Cytokine Inhibitors : TNF-α, IL-1,IL-2 antagonists

• Antibodies against specif ic 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

ISATX-247 Semisynthetic analogue of cyclosporine More potent, less nephrotoxic Less glucose intolerance In phase II clinical trial

Modif ied 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

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

Tolerogens

To induce T cel l 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 cl inical use t i l l nowPotential tolerogens in renal transplantation are:

Humanised anti -CD 80 Mab and Humanised anti-CD 86 Mab

Abatacept1 s t 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

BelataceptNewer CTLA4-Ig fusion proteinHigher affinity for CD 80/86 For kidney transplantationApproved in 2011

Helminthic therapy

Whipworm ova and hookworm used

Highly effective in relapsing-remitt ing mult iple 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

2. Modulation of dendrit ic cel l function

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

Immunostimulators

Cell based (Dendritic) therapyAntibody based therapyCytokine based therapyT cell adoptive transferAutologous immune enhancement therapyGenetically engineered T cellsImmune recoveryCheck point antibodies

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

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

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

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

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

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.

Immune recovery

CytokinesIL-7: for cancer and HIV patientsIL-2 : for HIV patients

Immune check point blockade

In normal physiology

PD=Programmed cell death 1

In cancer: there is up-regulation of PDL1 on cancer cellsMay 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

Eg: Nivolumab

Block PD-1, on the surface of activated T cells

In clinical tr ials

For treatment of cancer

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 t issues via interaction with its l igands, PD-L1 and PD-L2

Ipil imumab

•CTLA4 inhibitor: down regulates CTLA4 and increase immune system

•For metastatic melanoma, approved by USFDA in 2011

•Tried alone and with dacarbazine in phase II I tr ials-high survival rate was shown

•Undergoing tr ials 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

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

Tremelimumab

• Metastatic pancreatic cancer

• A ful ly human mab binding to CTLA4 on T cells

• Stimulates the immune system by blocking the CTLA4-negative regulatory signal

• Phase Ib tr ial

• Evaluating the safety, tolerabil ity, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer.

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