1. Group 6
Melinda Bachini, Thelma Brown, Jean Di Carlo-Wagner, Bob Riter, Chris Kinsinger, Keith Chan, Penny Blaisdell
IMMUNOTHERAPY

2. IMMUNOTHERAPY VACCINES CHECKPOINT INHIBITORS CART T CELL THERAPY
ADOPTIVE CELLULAR THERAPY
CART T CELL THERAPY
IMMUNOTHERAPY
Combination therapy>256,000

4. Preventative Vaccines
HPV
Hepatitis B
Inexpensive and widely effective (classic vaccine)

5. Treatment Vaccines
Makes immune system better able to identify cancer cells and to distinguish them as foe and not friend.
Uses patient’s own tumor cells to create personalized vaccine.
Provenge approved to treat metastatic prostate cancer. (2010)
Many clinical trials. Ovarian Cancer trial now in the news.
Incredibly labor-intensive and expensive.

6. CHECKPOINT INHIBITORS
An immune checkpoint inhibitors are drugs – often made of antibodies – that unleashes an immune system attack on cancer cells.

7. CHECKPOINT INHIBITORS

8. Immune Checkpoint Inhibitor Therapy PD1 or PDL1 (Removing the Brakes)
Activated T Cell
Deactivated T Cell
PD-1 is a checkpoint protein on immune cells called T cells. It normally acts as a type of “off switch” that helps keep the T cells from attacking other cells in the body. It does this when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack.
When programmed-death receptor (PD-1) on the T cell binds to programmed death-ligand 1 (PD-L1) on the tumor cell, the T cell becomes deactivated, allowing the cancer cell to evade immune attack

9. Immune Checkpoint Inhibitor Therapy
CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4)
CTLA-4 is another protein on some T cells that acts as a type of “off switch” to keep the immune system in check.
The CTLA-4 pathway is believed to regulate T-cell proliferation at the early stage of naive T-cell activation, principally in the lymph nodes. Activation of the CTLA-4 pathway downregulates the immune response by binding to CD80 (B7.1) or CD86 (B7.2).5
Inhibiting the CTLA-4 pathway:
Enhances T-cell activation and amplifies T-cell proliferation
Promotes the generation of memory T cells, thereby providing a long-term antitumor response

10. Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities
Infusion reactions
Endocrinopathies: thyroid, adrenal, hypophysitis
Rare (< 5%)
Pneumonitis
Grade 3/4 toxicities uncommon
Low grade reversible with steroids and discontinuation
Anemia
Toxicity less common than with anti–CTLA-4 but can be fatal
Occasional (5% to 20%)
Fatigue, headache, arthralgia, fevers, chills, lethargy
Rash: maculopapular, pruritus, vitiligo
Topical treatments
Diarrhea/colitis
Initiate steroids early, taper slowly
Hepatitis, liver/pancreatic enzyme abnormalities
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death-1; PD-L1, programmed death-ligand 1.
Weber JS, et al. J Clin Oncol. 2012;30: Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].

11. Summary of CTLA-4 Blockade Immune-Mediated Toxicities
Rare (< 2%)
Episcleritis/uveitis
Pancreatitis
Nephritis
Neuropathies, Guillain-Barré, myasthenia gravis
Lymphadenopathy (sarcoid)
Thrombocytopenia
Toxic epidermal necrolysis, Stevens Johnson syndrome
Toxicity related to ipilimumab appears to be dose related
Toxicity-related death occurred in < 1% of cases
Common (> 20%)
Rash, pruritus
Fevers, chills, lethargy
Diarrhea/colitis
Occasional (3% to 20%)
Hepatitis/liver enzyme abnormalities
Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death-1; PD-L1, programmed death-ligand 1.
Weber JS, et al. J Clin Oncol. 2012;30: Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].

12. Financial Toxicity
Combination therapy>256,000

14. CAR T cells are T cells from our immune system that are engineered to express T cell receptor that recognizes tumor specific antigen
enginer

15. These new T Cells are always active and  proliferate In the body and continue attacking cancer cells and specifically  killing the cancer .

17. Adoptive cell transfer therapy using tumor-infiltrating lymphocytes (TIL)
Rosenberg and Restifo, Science, Apr , 348 (6230): 62-68

18. NIH/NCI GI TILL Trial March 2012 – initial interview
Two weeks later lung wedge
4 tumors removed, cells harvested and grown
Return in April
Cell depleting chemo
Cell infusion
Recovery
Home

19. Results of first treatment
9th person to do trial
First with cholangiocarcinoma
First to have a partial response
Overall shrinkage of about 30%
Had no further treatment from April 2012 to October 2013
Enjoyed a great quality of life!
During this timeframe the mutation reactive t-cell was discovered.

20. Beginning of Round two….
New Discovery
Mutation reactive t-cell
Retreat with this t-cell
Excitement in the air
Beginning of Round two….

21. Cell Day!!!

22. Results from Second TIL Treatment
Achieved official partial response
Overall shrinkage of about 50-60%
Three years of GREAT quality of life
NO other treatments, just my immune cells working to keep cancer at bay.

24. Tumor regression after ACT with ERBB2IP-mutation-reactive Th1 cells
Cell Infusion
Cell Infusion
Jan. 11, 2016

25. Published Data

27. Privileged to meet more trial participants

28. 2016- A year to remember
Research shows mutation reactive t-cells are still present.
Same ERBB2IP mutation in tumors
Tumors are infiltrated with macrophages that express high levels of PD-L1
October – first dose of Pembrolizumab
November –second dose, scans show significant shrinkage!

29. New treatment plan

30. More Work to be Done VACCINES CHECKPOINT INHIBITORS
ADOPTIVE CELLULAR THERAPY
CART T CELL THERAPY