Targeted Therapies For Blood Cancers 2015 · Colorado Blood Cancer Institute . Targeted Therapy...

Immune and Targeted Therapies Including CAR T Cells for Blood

Cancers

Michael B Maris MD Director of Research

Colorado Blood Cancer Institute

Targeted Therapy

bull Therapy that takes advantage of molecular and genetic information to cause tumor cell kill by blocking key malignant cell function or by enhancing immunologic function

bull Specific (against tumor cell)

bull Reduces global toxicity to patient

bull More tolerable

bull More effective

bull More expensive

Targeted Therapy

1 Drug therapy

ndash Tyrosine Kinase Inhibitors

bull ABL ndash Imatinib dasatinib nilotinib

bull FLT-3 ndash Sorafinib Midostaurin

bull BTK ndash Ibrutinib

bull PI3K ndash Idelsilib IPI-145

ndash Small Molecules

bull BCL-2 inhibitor - ABT 199

bull Inhibition of transcription ndash BET inhibitor

Targeted Therapy

2 ImmunologicImmunotoxins Therapies

- Antibody

- CD 20 ndash rituxamab obinotuzamab

- CD 30 ndash brentuximab

- CD 33 ndash SGN CD33a

- Bifunctional

bull CD 19CD3 ndash Blinotumamab

Targeted Therapy

2 Cellular Therapies

- Chimeric Antigen Receptor (CAR) T Cells

- CD 19 ndash KiteJunoNovartis

- CD 20 ndash

- CD 33 ndash

- CD 138

Phase I Study ABT-199 in CLL






Targeted Therapy

1 Drug therapy


bull PI3K ndashIPI-145

25

Lymph Node Reduction in iNHL Patients with CT Scans

26

Progression-Free Survival (PFS)

27

Overall Survival (OS)

28

bull Median OS not reached

ndash 89 survival at 24 months (25 mg BID)

AE 25 mg BID

n=19 All Doses

N=36

ALTAST increase 2 (11) 4 (11)

Pneumonia

(combined)

1 (5) 2 (6)

Rash (combined) 1 (5) 2 (6)

Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)

Diarrhea 1 (5) 1 (3)

Stomatitis 1 (5) 1 (3)

Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)

Influenza 1 (5) 2 (6)

29

IPI 145 Toxicity

Targeted Therapy (AML)

1 Immunconjugate

ndash SGN CD33a

Targeted Therapy (ALL)

1 Bifunctional Immunconjugate

ndash Blinatumamab

Blinatumamab Engages Malignant Cells with Endogenous T cells

copy2014 by American Society of Clinical Oncology

Targeted Therapy (ALL and NHL)

1 CAR T cells

ndash anti CD19

Why Consider CAR T Cell therapy

bull Remarkable responses demonstrated in refractory B

cell malignances

bull Potential ability to target other malignancies with

suitable antigenic targets

bull Specialized activity need for cell processing and BMT

like capabilities to perform this therapy

bull Could replace the use of BMT for some indications

bull Patients will seek heme malignancy programs that can

offer this therapy

RIC Principle

Shift burden of tumor cell kill

from cytotoxic

Chemoradiotherapy

to

Donor T cells

Graft vs Tumor Effect

Thomas et al N Engl J Med 1981

copy2014 by American Society of Hematology

CAR T cells

bull Key element is production of T cells transfected with a

fusion protein with two main components

ndash Antigen recognition domain eg CD19

ndash T cell activation domaincostimulatory domains eg

CD28 costimulatory domain and T-cell receptor (TCR)

ndash T cell activation domains

bull Achieved through transduction into autologous T cells of

vectors with coding DNA


Kochenderfer JN et JCO AUGUST 2014

15 patients with advanced B-cell malignancies

9 diffuse large B-cell lymphoma (DLBCL)

2 indolent lymphomas

4 chronic lymphocytic leukemia

bull Patients received cyclophosphamide and fludarabine followed by a single

infusion of anti-CD19 CAR T cells

RESULTS

bull eight achieved complete remissions (CRs)

bull four achieved partial remissions one had stable lymphoma and

bull two were not evaluable for response

bull CRs were obtained by four of seven evaluable patients with

chemotherapy-refractory DLBCL

three of these four CRs with durations ranging from 9 to 22 months

Acute toxicities

bull fever hypotension delirium and other neurologic toxicities toxicities resolved

within 3 weeks after cell infusion

bull One patient died suddenly as a result of an unknown cause 16 days after cell

infusion

CAR T cells in NHL

9 months

Kochenderfer et al J Clin Oncol 2014 Aug 25

CAR T in NHL

James N Kochenderfer et al JCO 201533540-549

Results in ALL

Maude et al N Engl J Med 2014 3711507-1517October 16 2014

bull Autologous T cells transduced with a CD19-directed chimeric antigen

receptor (CTL019) lentiviral vector in patients with relapsed or refractory

ALL

bull Doses of 076times106 to 206times106 CTL019 cells per kilogram

Results

bull 30 children and adults received CTL019

bull Complete remission in 27 patients (90) 15 after prior stem-cell

transplantation

bull CTL019 cells proliferated in vivo and were detectable in the blood bone

marrow and cerebrospinal fluid

bull 6-month event-free survival rate of 67 and overall survival rate of 78

bull At 6 months the probability of persistence of CTL019 was 68 (95 CI

50 to 92)

bull Probability of relapse-free B-cell aplasia was 73 (95 CI 57 to 94)

RESULTS IN ALL

Cytokine-release syndrome

N Engl J Med 2014 3711507-1517October 16 2014

bull All the patients had the cytokine-release syndrome

bull Severe cytokine-release syndrome which developed in 27

of the patients

- was associated with a higher disease burden before infusion

bull Effectively treated with the antindashinterleukin-6 receptor

antibody tocilizumab

bull 30 treated in ICU

bull Not directly correlated with neurological toxicity

Toxicities of CAR T therapy bull Fever

bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological

bull B cell aplasia with hypogammablobulinemia

bull Tumor lysis syndrome

Cytokine Release Syndrome

Conclusion

bull Targeted therapy takes advantage of molecular and genetic information to cause tumor cell kill

bull There is an explosion of novel therapies that may help change the natural history of many aggressive blood cancers

bull Therapies include

1 Small molecules (TKI anti BCL2 BCR inhibitorshellip)

2 Immunconjugates bifunctional agent

3 CAR T cells

bull Agents have unique toxicities

bull Are likely to be very expensive

Targeted Therapy

bull Therapy that takes advantage of molecular and genetic information to cause tumor cell kill by blocking key malignant cell function or by enhancing immunologic function

bull Specific (against tumor cell)

bull Reduces global toxicity to patient

bull More tolerable

bull More effective

bull More expensive

Targeted Therapy

1 Drug therapy









Targeted Therapy


- Antibody




- Bifunctional


Targeted Therapy




- CD 20 ndash

- CD 33 ndash

- CD 138







Targeted Therapy

1 Drug therapy



25


26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



Targeted Therapy

1 Drug therapy









Targeted Therapy


- Antibody




- Bifunctional


Targeted Therapy




- CD 20 ndash

- CD 33 ndash

- CD 138







Targeted Therapy

1 Drug therapy



25


26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



Targeted Therapy


- Antibody




- Bifunctional


Targeted Therapy




- CD 20 ndash

- CD 33 ndash

- CD 138







Targeted Therapy

1 Drug therapy



25


26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



Targeted Therapy




- CD 20 ndash

- CD 33 ndash

- CD 138







Targeted Therapy

1 Drug therapy



25


26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells









Targeted Therapy

1 Drug therapy



25


26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



25


26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells




26


27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells




27


28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells




28



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



AE 25 mg BID

n=19 All Doses

N=36


Pneumonia

(combined)

1 (5) 2 (6)


Febrile

neutropenia

0 1 (3)

Neutropenia 0 1 (3)



Herpes zoster

(disseminated)

0 1 (3)

SAE 25 mg BID

n=19 All Doses

N=36

Pneumonia

(combined)

4 (21) 9 (25)

Pyrexia 1 (5) 5 (14)

Febrile

neutropenia

1 (5) 3 (8)


Nausea 1 (5) 2 (6)


29

IPI 145 Toxicity


1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells




1 Immunconjugate

ndash SGN CD33a



ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells





ndash Blinatumamab




1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells






1 CAR T cells

ndash anti CD19



cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells





cell malignances







offer this therapy

RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



RIC Principle


from cytotoxic

Chemoradiotherapy

to

Donor T cells




CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells






CAR T cells

















RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells











RESULTS







Acute toxicities




infusion

CAR T cells in NHL

9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



9 months


CAR T in NHL


Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells




Results in ALL




ALL


Results



transplantation





50 to 92)


RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



RESULTS IN ALL





of the patients







bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells




bull Hypotension

bull Pulmonary leak

bull Coagulopathy

bull Cytopenias

bull Renal changes

bull Neurological




Conclusion






3 CAR T cells



Conclusion






3 CAR T cells



Targeted Therapies For Blood Cancers 2015 · Colorado Blood Cancer Institute . Targeted Therapy...

Documents

Transcript of Targeted Therapies For Blood Cancers 2015 · Colorado Blood Cancer Institute . Targeted Therapy...