CAR T Cell Therapy for Multiple Myeloma - CelliconValley 2021 Alfred Garfall, MD 7 May 2021 - University of Pennsylvania
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C e l l i c o n Va l l e y 2 0 2 1 CAR T Cell Therapy for Multiple Myeloma Alfred Garfall, MD 7 May 2021
Disclosures
‣ Research funding to institution: Novartis, Janssen, Tmunity, CRISPR Therapeutics
‣ Honoraria: Janssen, GlaxoSmithKline, Amgen
2
On March 26, 2021, the Food and Drug Administration approved idecabtagene vicleucel
(Abecma, Bristol Myers Squibb) for the treatment of adult patients with relapsed or refractory
multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent,
a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA-approved
cell-based gene therapy for multiple myeloma.
3
BCMA Soluble BCMA
• Potential biomarker of MM disease burden
• Potential biomarker of anti-BCMA therapy activity
Gamma
secretase
MM patients treated with gamma secretase inhibitor
Pont et al., Blood. 2019 Nov 7;134(19):1585-1597 4
Hengeveld & Kersten, Blood Cancer Journal (2015) 5:282
T Cells Genetically Modified to Express an Anti–B-Cell A B S T R AC
Maturation Antigen Chimeric Antigen Receptor Cause BACKGROUND
Remissions of Poor-Prognosis Relapsed Multiple Myeloma From the Massachusetts General Hos- Preclinical studies suggest that bb2121, a chi
pital Cancer Center (N.R., M.V.M.), Beth therapy that targets B-cell maturation antigen
antigen with GSK2857916
Jennifer N. Brudno, Irina Maric, Steven D. Hartman, Jeremy J. Rose, Michael Wang, Norris Lam, Maryalice Israel Deaconess Medical Center ( J.R.),
Stetler-Stevenson, Dalia Salem, Constance Yuan, Steven Pavletic, Jennifer A. Kanakry, Syed Abbas Ali, Lekha and Dana–Farber Cancer Institute and ment of multiple myeloma.
Mikkilineni, Steven A. Feldman, David F. Stroncek, Brenna G. Hansen, Judith Lawrence, Rashmika Patel, Frances Veterans Affairs Boston Healthcare Sys- METHODS
tem (N.M.), Boston, and Bluebird Bio,
relapsed or refractory multiple
Hakim, Ronald E. Gress, and James N. Kochenderfer Cambridge (A.T., L.-P.L., R.A.M., K.F., M.M., In this phase 1 study involving patients with rela
F.P., M.T.Q.) — all in Massachusetts;
Sarah
we administered bb2121 as a single infusion a
Author affiliations and support information T h e n e w e ng l a nCannon
d j o uResearch
r na l oInstitute
f m e dic andi n e
Tennessee Oncology, Nashville ( J.B.); or 800×10 CAR-positive (CAR+) T cells in the
6
A B S T R A C T
Articles
ose escalation and expansion
(if applicable) appear at the end of this
article. Mayo Clinic, Rochester, MN (Y.L.); Hack- to 450×106 CAR+ T cells in the expansion phas
Purpose ensack University Medical Center, Hacken-
previous lines of therapy, including a proteasom
Published at jco.org on May 29, 2018.
Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be sack (D.S.), and Celgene, Summit ( J.W., tory agent, or were refractory to both drug class
Original Article
BCMA is a safe, validated target
G.R., Z.Y.) — both in New Jersey; Mount
Clinical trial information: NCT02215967. genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that Sinai Medical Center, New York (S.J.,
Corresponding author: James N. target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant D.M.); Stanford University Medical Cen- RESULTS
Kochenderfer, MD, NIH Bldg 10, Room plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our ter, Palo Alto (M.L.), and Celgene, San Results for the first 33 consecutive patients wh
Anti-BCMA CAR T-Cell Therapy bb2121
3-3330, Bethesda, MD 20892; e-mail: Francisco (T.C., K.H.) — both in Califor-
kochendj@mail.nih.gov.
knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). nia; and the Experimental Transplanta- ported. The data-cutoff date was 6.2 months aft
Targeting
s, Brandi Reeves, Edward ©B-cell
N Libby, Paul
2018 G maturation
Richardson,
by American antigen
Larry D Anderson
Society of Clinical Jr, with GSK2857916 Patients and Methods tion and Immunology Branch, National toxic effects were the most common events of gr
in Relapsed or Refractory Multiple Myeloma
Cancer Institute, National Institutes of
Sixteen patients received 9 3 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are Health, Bethesda, MD ( J.N.K.). Address (in 85% of the patients), leukopenia (in 58%), an
Soumi Lahiri, Zangdong He, DarenOncology
J Austin, Joanna B Opalinska, Adam D Cohen
antibody–drug conjugate in relapsed or refractory multiple
0732-183X/18/3622w-2267w/$20.00 reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty- reprint requests to Dr. Kochenderfer at (in 45%). A total of 25 patients (76%) had cyto
three percent of patients had MM refractory to the last treatment regimen before protocol Noopur Raje, M.D.,the
enrollment. Jesus Berdeja,Transplantation
Experimental M.D., Yi Lin, and M.D.,grade 1 or 2 in 23 patients (70%) and grade 3 in 2
Ph.D.,
myeloma (BMA117159): a dose escalation and expansion
E 36 • NUMBER 22 • AUGUST 1, 2018
T cells were transduced with a g-retroviral vector encoding CAR-BCMA. Patients Davidreceived M.D., Ph.D., Immunology
CAR-BCMA
Siegel, Sundar Branch, National Cancer occurred in 14 patients (42%) and were of grade 1
Jagannath, M.D., Deepu
Institute, National Institutes of Health,
Madduri, M.D.,
T cells after a conditioning chemotherapy regimen of cyclophosphamideMichaela and fludarabine.
Liedtke, M.D., Jacalyn Rosenblatt,
10–CRC–Rm. M.D., MarcelaMD (3%) had
V. Maus, M.D.,a reversible
Ph.D., grade 4 neurologic toxic e
OF Creceptor ofOthe
phase 1 trial
Bldg. 3-3888, Bethesda,
RNAL
ll-surface LINICAL NCOLOGY
tumour necrosis O R I
superfamily required G I N A L R E PLancet O R T
Oncol 2018; 19: 1641–53 Ashley Turka, Lyh-Ping20892,
Lam,orPharm.D.,
at kochendj@Richard 85%,Ph.D.,
A. Morgan,
mail.nih.gov. including 15 patients (45%) with complete
Results
on patient-derived myeloma cells and has emerged Theasoverall
a selective
response rate was 81%,
Published Kevin
with 63% very good partial response
Online Friedman,response.
or complete Ph.D., Monica
Drs. Massaro,
Raje, Berdeja,M.P.H.,
and Lin Julie Wang, had
contributed a complete
Pharm.D., response have had a relapse. The
Ph.D.,
Suzanne Trudel, Nikoletta Lendvai, Rakesh Popat, Peter M Voorhees, Brandi Reeves, Edward N Libby, Paul G Richardson, Larry D Anderson Jr, Greg ofRussotti, Ph.D., equally
Zhihong to thisPh.D.,
Yang, article. Timothy Campbell, 11.8M.D.,
months (95% confidence interval, 6.2 to 17.
Ph.D.,
Median event-free survival was 31 weeks. Responses included eradication extensive bone
e myeloma. WeHeather
assessed the
J Sutherland, Kweesafety, tolerability,
Yong, Axel Hoos, and
Michele M Gorczyca, preliminary
Soumi
marrow
November 12, 2018
Lahiri, Zangdong He, Daren J Austin, Joanna B Opalinska, Adam D Cohen
myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who Kristen Hege,
obtained anM.D.,
anti- Fabio Petrocca,
This article M.D.,onM.
was updated MayTravis (partial
Quigley,
8, 2019, response or better) and who could be e
M.S.,
http://dx.doi.org/10.1016/
tibody conjugated to microtubule-disrupting agent monomethyl and James N. Kochenderfer, (MRD) M.D. had MRD-negative status (≤10 nuclea
−4
MM response of partial response or better and had MM evaluable for minimal residual Nikhildisease at NEJM.org.
Munshi, M.D.,
Summary obtained bone marrow minimal S1470-2045(18)30576-X
residual disease–negative status. High peak blood CAR+ cell levels N Engl J Med 2019;380:1726-37. associated with responses, and CAR T cells pers
multiple myeloma.
T Background
Cells Genetically Modified
B-cell maturation antigen (BCMA) is toa cell-surface
Express an with
receptor
were associated Anti–B-Cell
of the tumour necrosis superfamily required Lancet Oncol 2018; 19: 1641–53
anti-MM responses. Cytokine-release syndrome toxicities were severe in DOI: 10.1056/NEJMoa1817226
See Comment
for plasma cell survival. BMCA is universally detected on patient-derived myeloma page
cells and has 1554 as a selective
emerged Published Online CONCLUSIONS
some cases but were reversible. Blood CAR-BCMA T cells were November predominantly highly differentiated A BS T R AC T
Copyright © 2019 Massachusetts Medical Society.
Maturation Antigen
antigen to be targeted Chimeric
by novel treatments Antigen
in multiple myeloma.Receptor
We assessed theCause
safety, tolerability, and preliminary
CD8 T cells 6 to 9 daysPrincess Margaret
after infusion. Cancer
BCMA +
12, 2018
antigen loss from MM was observed.
We report the initial toxicity profile of a BCMA
bel, first-in-human phase
clinical
Remissions 1
activity of study with
GSK2857916, dose
a novel
of Poor-Prognosis escalation
anti-BCMA (part
antibody
Relapsed 1) and
conjugated to microtubule-disrupting agent monomethyl http://dx.doi.org/10.1016/
Multiple Myeloma
Centre, Toronto, ON, Canada S1470-2045(18)30576-X
patients with relapsed or refractory multiple my
‣ Off-target or on-tumor/off-target toxicity has
auristatin F, in patients with relapsed and refractory Conclusion
multiple myeloma. BACKGROUND mented. (Funded by Bluebird Bio and Celgene;
SA, Canada, and the UK. Adults with
Jennifer N. Brudno, Irina Maric, Steven D. Hartman, Jeremy histologically or
CAR-BCMAcytologically
J. Rose, Michael T cells Wang, (Ssubstantial
hadNorris Trudel Lam, MD); Department
activity
From
Maryalice againstofheavily
the Massachusetts General
See Comment page 1554
treated Preclinical studiesMM.
Hos- relapsed/refractory suggest
Our that bb2121, a chimeric antigen receptor (CAR) T-cell
NCT02658929.)
Princess Margaret Cancer
cology GroupStetler-Stevenson,
performance
Methods We did an status
Dalia international,
Salem, Constance 0 ormulticentre,
1,Yuan,
andSteven progressive
open-label, results
Pavletic, should
first-in-human
Jennifer disease phase Medicine,
A. encourage
Kanakry, additional
1 study
Syed Abbas with pital
Myeloma
Ali, Cancer
development
dose LekhaescalationCenterof
Service, (N.R.,
(partCAR 1)M.V.M.), Beth therapy
T-cellCentre,
and therapies forCanadathat targets B-cell maturation antigen (BCMA), has potential for the treat-
MM.
not been conclusively identified.
Israel Deaconess Medical Center (J.R.), Toronto, ON,
Mikkilineni,
dose expansion Steven A. (part Feldman,
2) phases, David F. Stroncek,
at nine centresBrenna in the USA, G. Hansen, Canada, Judith andLawrence,
the UK. Adults Rashmika withPatel, Frances
histologically or cytologically ment of multiple myeloma. 1726
inhibitors, and immunomodulators were recruited Memorial Sloan Kettering (S Trudel
and MD); Department of n engl j med 380;18 nejm.org May 2
J for
Clin this Groupstudy.
and Dana–Farber Cancer Institute
Hakim, Ronaldmultiple E. Gress,myeloma, and JamesEastern N. Kochenderfer Oncol 36:2267-2280. © 2018 byand American Society of Clinical
confirmed
CLINICAL MEDICINE
Cooperative Oncology performance status
TheCancer
Journal Center,
0 orVeterans
1,
of ClinicalNew
progressive
Affairs
York, Boston
Investigation
disease
NY, HealthcareMemorial Sys- Oncology
Medicine, Myeloma Service,
The New England Journal of Medicine
mg/kg) through after 1 hstem intravenous infusions
‣ However, some central and peripheral
cell transplantation, alkylators,once proteasome every 3 weeks.
inhibitors, In USA (N Lendvai
and immunomodulators were
tem recruited
(N.M.), Boston, for this Bluebird Bio, METHODS
andstudy. Sloan Kettering
d support information In part 1, patients received GSK2857916 (0·03–4·60 mg/kg) through 1 h intravenous infusions CambridgeMD);
once (A.T.,
every L.-P.L.,
3 R.A.M.,In
weeks. K.F.,Cancer
M.M.,Center, In New York, NY,
this phase 1 study involving patients with relapsed
Downloaded from nejm.org on March 28, 2021. For personal use only. No o
or refractory multiple myeloma,
antigen CD19 have established efficacy in
phase 2thisdose ofpart GSK2857916 (3·40 mg/kg)
A B S
once T R
everyA C
3 Tweeks. USA (N Lendvai MD); Copyright © 2019 Massachusetts Medical Society. All rig
B cell maturation antigen–specific CAR T cells are
at the end of
INTRODUCTION Department F.P., M.T.Q.) — all in Massachusetts;
of Medicine,
2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks.10-14Department
leukemia Institute and
we administered
of Medicine,
and lymphoma.
15-19
Thebb2121
success as a single infusion at doses of 50×106, 150×106, 450×106,
d Mayrecommended Purposephase 2 dose. Secondary endpoints for part 2 Weill Medical
Primary endpoints were maximum tolerated dose and recommended phase 2 dose.
Sarah Cannon Research
Secondary College,Oncology,
Tennessee nervous system toxicities are emerging in
endpointsCornell for part
of anti-CD19 2 Weill
Nashville (J.B.);
Medical
CAR T-cell or 800×10
College, Cornell
therapies
6
CAR-positive
against leuke- (CAR+) T cells in the dose-escalation phase and 150×106
on
patients
29, 2018.
Therapies clinically active in multiple myeloma
includedwith
who genetically
received one
novel mechanisms
preliminary
or
anti-cancer clinical
more
of action
doses
are needed
activity.
were
All Multiple
included
for multiple
patients whomyeloma
in
received
this
B cell
myeloma (MM) one (MM).
or
maturation
University, anT almost
is more cells
doses
New
Mayo can were
York,
Clinic,
always
antigen–specific
be Rochester,
included
NY, USA
mia in this
MN
and
University, New York, CAR NY, USA T cells are clinically
(Y.L.); Hack- to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three
lymphoma has encouraged development
CAR T and bispecific antibody studies.
(N Lendvai); NIHR University
ion: NCT02215967. prespecified modified to express
administrative chimeric
interim analysis antigen(datareceptors
cutoff date(CARs),
incurable June 26,which
2017),
malignancy active are
which artificial
of (N was
plasma indone proteins
cells. that myeloma
forIninternal
ensack
multiple University
recent purposes.
Medical Center,This Hacken- previous
Hospital lines of therapy, including a proteasome inhibitor and an immunomodula-
5,20-23
target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal Lendvai);and NIHR
sack
malignant University
3 (D.S.),
of CARs
and Celgene, Summit
College London
targeting
(J.W., MM.
ff date June 26,
or: James N. Adam2017),
study D. is
Cohen, which
registered
1
Alfred L. was
withGarfall,
ASSOCIATED done
ClinicalTrials.gov,
1
Edward
CONTENT for
A. internal
number
Stadtmauer, 1
J. purposes.
NCT02064387,
Joseph
years, Melenhorst,
several and
2
This
Simon
new is ongoing,
F. Lacey,
therapies
2 but closed
Eric
for Lancaster,
MM for
have recruitment.
Dan T.
pro- Vogl, 1
B-cell
Clinical Research Facility, NHS
maturation tory
antigenagent, or wereisrefractory
(BCMA) a mem- to both drug classes. The primary end point was safety.
M.College London toHospital
G.R., Z.Y.) — both in New Jersey; Mount
NIH Bldg 10, Room plasma
Brendan cellsM. Weiss, but1 Karen
not normal Dengel,2 essential
Annemarie cells. Nelson,We 2 conducted
Gabriela Plesa,2 Fang theChen, Megan
first-in-humans
2
Davis,clinical
2
Wei-Tingtrial,Hwang, our4, Carl Foundation Trust, London, UK
T02064387,
MD 20892; e-mail:
ov.
and is
knowledge,
Findings
Regina M. ongoing, of
Between
Young, 2T cells but
Jennifer July L. 29, closed
Listen to 5the podcast
expressing2014,
Brogdon,
by Dr Becker at
a
and
Randi for
CARFeb
Isaacs, recruitment.
targeting
21, 5
2017,
Iulian weBCMA
longed(CAR-BCMA).
treated
Pruteanu-Malinici,
survival
73
of patients
patients:
5
Don
Adam
L. 38
with
patients
Siegel, 2,6
D.
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Bruce
MM, Sinai
Cohen,
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but 2,6cure
Research
Levine,
Medical
…
dose-escalation
for Center,
Facility, NHS berH.ofNew
part
D.M.); Stanford University MedicalLevine 1the
June,
and
York
tumor (S.J.,
necrosis
Michael
(R Popat MD, K Yong
Cen-Cancer
factor
C. MD); superfamily; BCMA
RESULTS Atrium
Milone
35H.patients
Carl June,2,6 and in Michael
the dose-expansion
C. Milone 6
part 2. There wereMM remains elusive.
no dose-limiting toxicitiesMMand therapies
no maximum with Palonovel tolerated is dose
found was on MM cells,Institute,
normal plasma cells, and
n Society of Clinical Patients and Methods ascopubs.org/jco/podcasts Foundation
J Clin Invest. Trust,
ter,
2019;129(6):2210-2221. London,
Alto
1-4
(M.L.), UKand Celgene, San Charlotte,
Health,
https://doi.org/10.1172/JCI126397. Results for the first 33 consecutive patients who received a bb2121 infusion are re-
NC, USA
identified in part 1. On the basis 6 of safety and clinical mechanisms
activity, we of
selected action
3∙40 continue
mg/kg as to
the be needed.
Francisco
recommended (T.C., K.H.)
phasea small
—2 both
dose. subset of
in Califor- normal
(P M Voorhees B cells; BCMA is not
MD); Lineberger
Sixteen patients
Abramson Cancer
1
Center, Centerreceived
2
9Data 10 Department
for Cellular Immunotherapies,
3
3 Supplement CAR-BCMA T cells/kg
of Neurology, and
4
Department ofat the highest
Biostatistics, dose
Epidemiology and level
(R
Informatics, of the
Popat
University trial;
MD, K
of Pennsylvania, we
Yong are MD);
Philadelphia, Pennsylvania, ported. The 5,20,24-28
data-cutoff date was 6.2 months after the last infusion date. Hematologic
treated 73 patients: USA.Corneal
reporting 38events
results
Novartis Institute
5 patients
ofwere
these
for Biomedical common
Research, 16 in the
(20 [53%]
patients.
Cambridge,
DOI: dose-escalation
The
Massachusetts,6
USA.of 38 patients
patients
Department
https://doi.org/10.1200/JCO. ofhad ainmedian
Pathology part
and A part
chimeric
1 and
Laboratory of 9.51 University
22
Medicine, and
antigen
[63%]
prior ofof
lines
receptor
35ofMedicine
inMM
Pennsylvania, (CAR)
parttherapy. nia; and is
2);Pennsylvania,
Philadelphia, most (18a
Sixty-
the
USA. fu- Experimental
[47%] Oncology expressed
in part 1 and Transplanta-
on other
Comprehensivenormal
toxic
Cancer cells.
Center,
effects
This fa-
were the most common events of grade 3 or higher, including neutropenia
Levine Cancer tionInstitute, Atrium
Clinical Clinical trials
w-2267w/$20.00 and Immunology Branch, NationalUniversity of North Carolina,
19 [54%] in ofpart 2) werehad grade 1 or 2 and resulted in two sion protein
treatment containing
discontinuations T-cell–signaling anddomains
in partenrollment.
1Cancer noInstitute,
discontinuations in
vorable Institutes
expression pattern led us to develop the first
no dose-limiting three toxicities
percent
part were
2. Thetransduced
patients
most common
and no MM
grade
maximum
2018.77.8084 refractory
3 or 4 events
to the tolerated
last treatment dose was
regimen before
[34%]Health,
protocol
Charlotte,
5-9T cells NC, 1 USA
National of
Chapel Hill,(in 85%
NC, USA 20 of the patients), leukopenia
maturation(in 58%),(BCMA)
anemiais(in 45%), and thrombocytopenia
vectorwere thrombocytopenia
andCAR-BCMA.
an antigen-recognition (13 of 38moiety.
patients inTpart
Health, cells
Bethesda,and 12 [34%]
reported
MD (J.N.K.).of
anti-BCMA
Address CARs. We of tested one of the
BACKGROUND. CAR are a promising therapy for hematologic malignancies. B cell antigen
T cells DOI:with a g-retroviral
https://doi.org/10.1200/JCO.2018. encoding Patients received
target inCAR-BCMA
(B Reeves MD); University
(inSeattle,
45%). A total of 25 patients (76%) had cytokine release syndrome, which was of
tivity, we selected 35 in3∙40
part
T cells BACKGROUND. 2) mg/kg
and
after a conditioning anaemia
77.8084 as
CAR T cells are
(6the[16%]
chemotherapy recommended
in part
a promising therapy
1 and
regimen 5 [14%]
for hematologic
phase
in part
transduced
of cyclophosphamide 2). 2
There
withdose. were
malignancies. B cell maturation
12
a rational
CARs (P
directed M
and fludarabine. Voorhees
treatment-related
against
antigen (BCMA)
MD);
reprint
multiple
the Lineberger
serious
requests
myeloma
B-cell adverse
to(MM). events
Dr. Kochenderfer
anti-BCMA CARs at that
Washington, we designed
WA, USA (CAR-BCMA)
and no treatment-related deaths. In part 2, 21 (60∙0%; 95% CI 42∙1–76∙1)METHODS. of 35 patients theis Experimental
a Transplantation(E Nand grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects
Weachieved ana overall Iresponse.
Libby MD); Dana-Farber
n part 1 and 22 [63%]
Results rationalof target35in multiple
in part myeloma 2);(MM). most (18 [47%] in part 1 and Comprehensive Immunology
conducted Cancer phase Center,
Branch, studyNational Cancer
of autologous
occurredin in
Cancer Institute,
T cells Boston, MA,14transduced
lentivirally
patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient
with a fully human, BCMA-specific
TheInterpretation
overall response rate was 81%, with 63% very good partial response or University
complete
CAR containing CD3ζ
of North
Institute,
response.
and 4-1BB
Carolina,
National
signalingInstitutes ©
domains of Health,
2018 by
USA American
(P G Richardson
(CART-BCMA), Society
MD);ofsubjects
Clinical Oncology 2267
with relapsed/refractory MM. Twenty-five
5
o treatment discontinuations METHODS. WeAt the in
conducted apart
phase
identified I 1
studyandof
recommended no
autologous discontinuations
T cells lentivirally
phase 2 dose, GSK2857916 transduced in
with a fully human,
was were BCMA-specific
well treated
toleratedBldg.
CAR
and
in 310–CRC–Rm. hadas good3-3888,clinical
Bethesda, 1,MD
cohortUniversity (3%) to 5 × 10 CART-BCMA cells 4
of Texas
8 had a
8 reversible grade neurologic
cohort 2,toxic effect. The objective response rate was
Median event-free survival was 31 weeks. Responses included eradication Chapel Hill,
ofTwenty-five
extensive NC, USA
bone
subjects cohorts follows: 1 × 10 alone;
activitycontaining
in heavily CD3ζ and 4-1BB signaling
pretreated domains
patients, (CART-BCMA),
thereby indicating in subjects that with this relapsed/refractory
might MM.
be a promising subjects
candidate
20892, for
org/m the
at kochendj@treatment mail of5.gov.
.nih Southwestern, 85%, including
Dallas, TX, USA cohort15 patients (45%) with complete
8 to 5 ×responses. Six of the 15 patients who
rombocytopenia (13 [34%] 3of 38 aspatients 1,in part 18 CART-BCMA
and 12from [34%] of
2 7 to 7 CART-BCMA 2 plus 8
marrow myeloma
treated in and resolutionfollows:of soft-tissue toplasmacytomas. Allalone;
11 patients who obtained an anti-
cyclophosphamide (Cy) 1.5 plus 1 × 10 × 10 cells; 3, Cy 1.5 g/m 1 × 10 10
were cohorts cohort 1 × 10 8
5 × 10 cells cohort 2, cyclophosphamide (Cy) 1.5 g/
relapsed or refractory multiple myeloma. Downloaded ascopubs.org CART-BCMAby(B Reeves
100.34.240.67
cells. MD);
No University
onprespecified
Drs. March
Raje, 28, 2021
Berdeja,
ofand
BCMA fromLin (L D level
100.034.240.067
contributed
expression Anderson had
was Jr MD); Vancouver response have had a relapse. The median progression-free survival was
a complete
required.
MM response m2 plus 1 × 10 of7 topartial responsecells;
5 × 107 CART-BCMA or cohort
better 3, Cy and1.5 g/m had MM
plus 1 × 10evaluable
to © 5 ×2021 for minimal
108 CART-BCMA cells. residual
No prespecifieddiseaseBCMA
in part 2). There were 12 treatment-related serious
2
adverse
8
obtained expression
bone level was required.
marrow minimal residual disease–negative
Copyright
status.
events
High
American
peak
Society
Washington,
blood CAR
of Clinical
+
cell
Oncology.
Seattle,
equally to
levels
thisWA, All
USA
article. rights reserved. General Hospital, Vancouver,
BC, Canada11.8 months
(H J Sutherland MD);(95% confidence interval, 6.2 to 17.8). All 16 patients who had a response
Funding GlaxoSmithKline. (partial response or better) and who could be evaluated for minimal residual disease
95% CI 42∙1–76∙1) of 35CART-BCMA patients achieved anCytokine-release
overall response. (E N Libby MD); Dana-Farber
RESULTS. CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release
GlaxoSmithKline, Philadelphia,
were associated
RESULTS. with anti-MM cells were responses.
manufactured and expanded in all subjects. syndrome
Toxicities includedtoxicities
syndrome cytokineandwererelease severe
This article
syndromewhich
neurotoxicity, in was updated on
were grade 3–4 in May 8, 2019,
8 (32%) and 3 (12%) subjects, respectively, and reversible. One
PA, USA (A Hoos MD,
some cases
and but
neurotoxicity,were reversible.
which were grade Blood
3–4 in 8 CAR-BCMA
(32%) and 3 (12%) T cells
subjects, were predominantly
respectively, and Cancer
reversible. highly
One Institute, fromBoston,
at NEJM.org.
differentiated
atsubject died MA, (MRD) had MRD-negative statuscytokine
(≤10−4release
nucleated cells). CAR T-cell expansion was
Copyright © 2018 Elsevier Ltd. All rights reserved. M M Gorczyca MS, S Lahiri PhD,
subject died day 24 candidemia and progressive myeloma, following treatment for severe
CD8+ Tatcells day 24 6 fromto candidemia
9 days after infusion.
and progressive BCMAfollowing
myeloma, antigen loss from
treatment for severe MM wasrelease
syndrome
cytokine observed.
USAsyndrome(P G Richardson
and
N Engl J Med MD);
and encephalopathy. Responses (based on
2019;380:1726-37. PhD, J Bassociated
Z Hetreated Opalinska
subjects) withseen
MD);were responses,
in 4 of 9 and
(44%)CAR T cells
in cohort 1, 1persisted
of 5 up to 1 year after the infusion.
2 dose, GSK2857916
Introduction
Conclusion wasResponses
encephalopathy. well (basedtolerated and were
on treated subjects) had seen good clinical
in 4 of 9 (44%)
(20%) in cohort 2, and 7 of […]
DOI:and
in cohort 1, 1 of 5 (20%) in cohort
of differentiation, University of 2,
including plasma
10.1056/NEJMoa1817226
Texas 7 of GlaxoSmithKline, Uxbridge, UK
cells. Mice without (D J Austin PhD); 2
CONCLUSIONS
and Abramson
11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing atCopyright © 2019 Massachusetts Medical Society.
11, 14, and
ng that this might32be
CAR-BCMA
Progress a promising
T
in
months.
cells had
immunotherapy candidate
substantial
has
Decreased BCMA expression
activity
substantially forcellsthe
against
on residual MM
improved treatment
heavily
was noted
treated
expression of Southwestern,
relapsed/refractory
of BCMA
in responders; expression
have a MM.
reduced Our
number
Dallas,
increased at progression
of
in TX, USA
long-lived Cancer Center, University of
We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for
Pennsylvania, Philadelphia, PA,
results should encourage
the prognosis additional
for patients with development of CAR
multiple myeloma. 1
T-cell
bonetherapies
marrow plasma for MM.cells, but–have+ an+ otherwise normal
(L D of
most. Responses and CART-BCMA expansion were associated with CD4/CD8 T cell ratio 3and frequency Anderson Jr MD);
CD45RO CD27 CD8 Vancouver patients
USA (A D Cohen MD) with relapsed or refractory multiple myeloma. Antitumor activity was docu-
However, outcomes remain poor for those with relapsed phenotype. BCMA membrane expression is present on a
T cells in the premanufacturing leukapheresis product. mented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number,
and refractory disease. Patients who are refractory to subset of normal late-stage B cellsVancouver,
J Clin Oncol 36:2267-2280. © 2018 by American Society of Clinical Oncology General Hospital, and is universally Correspondence to:
Dr Suzanne Trudel, Princess
Idecabtagene Vicleucel
‣ Autologous anti-BCMA CAR T cell with 4-1BB costimulatory domain
‣ Phase 2 study (KARMMA)
• 3 prior regimens including a thalidomide analog, proteasome inhibitor, and anti-CD38 Ab
• 140 enrolled, 128 treated, 1 unsuccessful manufacturing
• Cy/flu 300/30 x 3 lymphodepletion
• Dose: 150 (N=4), 300 (N=70), or 450 (N=54) x 106 cells
• 84% triple-refractory, 26% penta-refractory
6
Munshi, Anderson, Shah et al., N Engl J Med 2021; 384:705-716
Idecabtagene Vicleucel
Similar RR in patients with…
• Triple- and penta-refractory MM
• Extramedullary disease
• High-risk cytogenetics
• High disease burden (>50% BM)
7
Munshi, Anderson, Shah et al., N Engl J Med 2021; 384:705-716
Idecabtagene Vicleucel
8
Munshi, Anderson, Shah et al., N Engl J Med 2021; 384:705-716
Idecabtagene Vicleucel
‣ Cytokine release syndrome:
• 84% overall, 4% G3, N=1 G4, N=1 G5
• 96% of patients at 450x106 dose
• Median onset day 1 (range 1-12), median duration 5d
‣ Neurologic toxicity:
• 18% overall, 3% grade 3, no grade 4/5
• Median onset day 2 (range 1-10), median duration 3d
9
Idecabtagene Vicleucel
‣ 97% had rising soluble BCMA at time of disease progression
‣ 4% of patients with suspected BCMA loss at progression (1 with proven bi-alleleic BCMA loss)
10Ciltacabtagene autoleucel Binding domains
‣ Camelid-derived tandem single-domain BCMA binders
‣ CARTITUDE-1 study (Phase 1b/2) (N=97)
VHH VHH
ORRa: 96.9% (94/97)
100%
4-1BB
80% Frequency in Frequency in
N evaluable patients all treated
sCR: n=57c n=97d
60% 67.0%
67.0% CD3z
Patients
≥VGPR: Overall MRD- 53 93.0% 54.6%
92.8%
40% MRD- and sCR 33 57.9% 34.0%
MRD- and ≥VGPR 49 86.0% 50.5%
20%
25.8%
0% 4.1%
Best responseb = sCR VGPR PR
11
62nd ASH Annual Meeting 2020, Madduri D et al. #177Ciltacabtagene autoleucel
‣ Camelid-derived tandem single-domain BCMA binders
‣ CARTITUDE-1 study (Phase 1b/2) (N=97)
12-month PFS
sCR: 84.5% (95% CI, 72.0–91.8)
VGPR: 68.0% (95% CI, 46.1–82.5)
Median PFS not reached in either group
No. at risk
sCR 65 65 62 53 27 12 2 1 1 0
VGPR 25 24 19 15 3 2 0 0 0 0
12
62nd ASH Annual Meeting 2020, Madduri D et al. #177Cilta-cel: Cytokine Release Syndrome
Maximum CRS Grade (N=97)
49 (51%)
38 (39%)
5 (5%) 3 (3%) 1 (1%) 1 (1%)
No CRS Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
§ CRS onset
̶ Day 4 or later: 89.1% (n=82)
̶ Day 6 or later: 73.9% (n=68)
§ CRS resolved in 91 (98.9%) patients within 14 days of onset
13
62nd ASH Annual Meeting 2020, Madduri D et al. #177Cilta-cel neurologic toxicities
‣ ICANS ICANS
Other
neurotoxicities
• Any grade: 16 (16.5%)
Time to onset,
• Grade ≥3: 2 (2.1%) median (range) days 8 (3–12) 27 (11–108)
• Resolved in all patients Time to recovery, median
4 (1–12) 75 (2–160)
‣ Other neurologic toxicities (range) days
• Any grade: 12 (12.4%)
• Grade ≥3: 9 (9.3%)
• 5 pts: movement and/or neurocognitive
• 7 pts: nerve palsy, peripheral motor neuropathy
• Outcomes
– 1 ongoing
– 1 died due to neurotoxicity complications
– 4 died due to other problems
AE, adverse event; CAR-T, chimeric antigen receptor T cell; CRS, cytokine release syndrome; ICANS, immune effector cell–associated neurotoxicity syndrome.
a Events not reported as ICANS [ie, onset after a period of recovery from CRS and/or ICANS]).
1414
62nd ASH Annual Meeting 2020, Madduri D et al. #177Other phase 1/2 autologous BCMA CAR T cell studies
Abstract Product n ORR CR Comment
ASCO
orva-cel 62 92% 36% 1:1 CD4:CD8 ratio, Tcm-enriched
8504
ASH 130 bb21217 69 68%* 29% PI3K inhibitor during manufacturing
ASH 133 CT053 20 94% 28% 8-10 day manufacturing
Transposon-based, Tscm+Tcm-enriched. Single and
ASH 134 P-BCMA-101 55 60%** ?
serial administration. Combos w/ ritux and len
Dual BCMA/CD19 CAR. 24-36 hour
ASH 178 GC012F 16 94% 56%
manufacturing
ASH 498 FHVH-BCMA-T 20 90% ? heavy chain-only binding domain
*84% (16/19) ORR w/ new manufacturing process
**original manufacturing process (n=30)
Mailankody et al, ASCO 2020, #8504; Alsina et al, ASH 2020, #130; Kumar et al, ASH 2020, #133; Costello et al, ASH 2020, #134;
15
Jiang et al, ASH 2020, #178; Mikkilineni et al, ASH 2020, #498 Slide courtesy of Dr. Adam CohenAnti-BCMA/CD3 bispecific antibodies
AMG701
PF-06863135
Teclistamab
EM801
AMG-420
CC-93269/EM901
REGN5458
HPN217
TNB-383B
AFM26
16
Image from Shah et al. (2020) Leukemia 34:985Full-size anti-BCMA/CD3 bispecific antibodies
‣ Teclistamab, weekly subcutaneous dosing
‣ At most active IV/SC cohorts: 69% ORR, 94% of responses ongoing after mF/U 6.5 months
Garfall et al., ASH 2020, abstract 180 17Bispecific antibodies against other targets
‣ Talquetamab: anti-GPRC5D/CD3 (Chari et al., ASH 2020 abstract #290)
• Dysgeusia as a notable AE
• ORR 66% at active doses
‣ Cevostamab: anti-FCRH5/CD3 (Cohen et al., ASH 2020 abstract #292)
• ORR 61% at active doses
18Summary
‣ Very exciting time for multiple myeloma immunotherapy
‣ Ide-cel: FDA-approved anti-BCMA CAR T cell
‣ Other potent anti-BCMA CAR T cells are in clinical development
‣ Response durability remains a challenge; in vivo activity of CAR T cells appears limited
‣ Most patients progress with BCMA+ disease à potential for serial anti-BCMA therapies
‣ Neurologic toxicity may accompany more potent therapies
‣ Bispecific antibody responses rival CAR T cell responses
‣ New cell-surface targets: GPRC5D and FCRH5
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