1. Immunotherapy for lymphoma: The time is now
Justin Kline, M.D.
Assistant Professor, Department of Medicine
Committees on Immunology and Cancer Biology
University of Chicago Comprehensive Cancer Center

2. Outline
Nuts and bolts of the immune system and how it recognizes and attacks cancer cells?
Cancer immune escape.
Types of cancer immunotherapy.
Clinical results of immunotherapy for lymphoma

3. The immune system
Evolved to provide protection against viruses and bacteria
Immune cells are created from bone marrow stem cells
Consists of cells and proteins whose purpose is to recognize and kill micro-organisms
The immune system is “educated” to attack foreign invaders, but at the same time, leave healthy, self-tissues unharmed
The immune system can sometimes recognize and kill cancer cells
2 main branches
Innate immune system – Initial responders
Adaptive immune system – Tailored attack

4. Immune cells develop in the bone marrow
Innate immune cells
Adaptive immune cells

5. How T cells recognize their targets
Antigen – a substance recognized by receptors on immune cells

6. How are cancer cells seen as “abnormal” by the immune system?

7. Cancers can effectively “hide” from the immune system
- Reversing cancer-induced immune escape pathways can re-awaken the immune system to fight cancer

8. The PD-1 / PD-L1 axis in cancer

9. Cancer immunotherapy makes its mark
Immunotherapy – Treatments that take advantage of the immune system to fight cancer

10. Immunotherapy for lymphoma - approaches
Cancer vaccines
Anti-idiotype vaccines
Adoptive T cell therapy
Chimeric antigen receptor (CAR) therapy – genetically engineered T cells that can recognize cancer cells (CD19)
Immune checkpoint blockade
PD-1 blockade therapy

11. CAR T cell therapy for lymphoma

12. CAR T cell therapy for lymphoma
Kochenderfer et al., Nat Rev Clinical Oncology 2013

13. Advantages of CAR T Therapy
One-time infusion
Universal application. Nearly all non-Hodgkin lymphomas have the target (CD19 protein)
CAR T cells can be made to recognize almost any target on cancer cells
CAR T cells can be manufactured quickly (2-3 weeks)
CAR T cells grow rapidly and kill lymphoma cells quickly and efficiently
CAR T cells persist for months (or longer). They have MEMORY
Slide contributed by Sergio Giralt

14. CAR T cell therapy - toxicities
Cytokine release syndrome (CRS)
Results from release of proteins called “cytokines” from activated CAR T cells
Can be mild (fever) or life-threatening (hypotension, pulmonary edema)
Treatment: IL-6 or IL-6R blocking antibodies (tocilizumab, siltuximab) and corticosteroids
Neurological toxicity
Acute
Delayed
Cerebral edema (most feared, often fatal)
Treated with steroids
Both CRS and neurotoxicity have become more manageable with early recognition and intervention
Slide developed by E Squared Communications based on WG discussion
1. Teachey DT et al. Cancer Discov. 2016; 6(6); 664–79.

15. Axi-Cel (Axicabtagene Ciloleucel)
Pivotal phase 1/2 study:
ZUMA-1
Patients enrolled:
DLBCL (76%) , t-FL (16%), PMBCL (8%)
Refractory disease to most recent therapy or relapse < 1 year after autologous transplantation
Response Rates
N=101
OR rate
72%
CR Rate
51%
PR Rate
21 (21%)
Duration of Response
N=73
Median
9.2 months
Range
0.03, 14.4+
Median follow-up
7.9 months
YESCARTA [package insert]. Santa Monica, CA: Kite Pharma, Inc.; 2017.
Neelapu SS, et al. N Engl J Med Dec 28;377(26):
Neelapu et al, NEJM 2017

16. CAR T cell therapy is remarkably effective in DLBCL
4 weeks after CAR T therapy
Neelapu et al, NEJM 2017

17. Checkpoint Inhibition as Cancer Immunotherapy
Drake et al, Nat Rev Clin Oncol 2014

18. PD-1 blockade is effective in relapsed Hodgkin lymphoma
Nivolumab treatment of 23 patients with relapsed HL
80% had prior stem cell transplant, and 80% received brentixumab
Response rate was 87% (17% complete response rate)
86% in remission at 6 months
Few serious side effects
Ansell et al, NEJM 2015

19. Conclusions The immune system can recognize and kill cancer cells
Cancers express antigens that can be seen as “foreign” to T cells of the immune system
Although immune responses are generated against lymphoma in some patients, they are suppressed and ineffective
3 main types of immunotherapy for lymphoma are: vaccines, CAR T cell therapy and PD-1 blockade
CAR T cell therapy for B cell lymphomas is very effective, but complex, expensive and can be associated with severe side-effects
PD-1 blockade therapy works well in Hodgkin lymphoma and in some NHLs. It is easy to administer and is relatively safe
Immunotherapy has revolutionized the way we treat cancer. More to come….