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SADELAIN ET AL
CAR T cell infusion, 16 patients had morphologic disease (
5% blasts in brain marrow) and the remaining 16 patients
had minimal residual disease (MRD). Thirteen out of sixteen
patients with morphologic disease (81%) and 16/16 patients
with MRD (100%) were in complete remission (CR) after the
19–28z CAR T cell infusion, yielding an overall CR rate of
91% (29/32 patients). Of the 28 evaluable patients with
MRD, the MRD negative CR rate was 82%. Eleven patients
underwent alloSCT following the CAR T cells infusion. As
of January 25, 2015, the median follow up was 5.1 months
(range, 1.0 to 37.6 or longer), with 14 patients having at
least 6 months of follow-up. The 6-month overall survival
(OS) rate of all patients was 58% (95% CI, 36 to 74). Among
the patients who achieved CR, OS at 6 months for patients
who had alloSCT versus no alloSCT following CAR T cell
infusion was 70% (95% CI, 33 to 89) and 61% (95% CI, 29 to
82; p 0.30), respectively. Two patients relapsed with CD19-
negative disease (6%).
The two main safety concerns associated with the use of
CARs are the targeted destruction of normal tissues and
strong cytokine responses occurring in a subset of patients,
now referred to as severe cytokine release syndrome
(sCRS). 19 The immune-mediated rejection of normal tissues
that express the targeted antigen (referred to as an on-target,
off-tumor response) results in B cell aplasia in the case of
CD19 CAR therapy. B cell aplasia can be effectively managed
by administering intravenous immunoglobulin. Furthermore,
B cell aplasia is reversible following the disappearance
of CAR T cells and after bone marrow transplantation. It remains
an issue in those few patients who show very longterm
persistence of the CAR T cells.
The second major concern is that of sCRS, which is associated
with intense antitumor responses mediated by large
numbers of activated T cells. These typically cause high fever
(38°C for 3 days), hypotension, respiratory distress,
and/or neurological symptoms (in particular confusion,
aphasia, or global encephalopathy). Management of these
symptoms may require steroids, interleukin-6 receptor
blockade (tocilizumab), vasopressors, and/or supportive
therapy delivered in the intensive care unit. Importantly, we observed
in our fırst fıve patients 17 and later confırmed in the fırst
16 patients 19 that the likelihood of developing sCRS is tightly
correlated with tumor burden, thus providing a simple means to
anticipate patients who are at risk of developing sCRS. This has
proven true in pediatric patients. 18,20,21,23 In a study of 33 adult
patients who all had high tumor burden, sCRS requiring vasopressors
or mechanical ventilation for hypoxia occurred in 7 patients
and was effectively managed with IL-6R inhibitor and/or
corticosteroid therapy. Other approaches to treat or prevent
sCRS are reviewed elsewhere. 23-25
PERSPECTIVE
The past 2 decades have seen the creation of a new toolbox of
recombinant receptors for cancer immunotherapy. Second
generation CARs have transformed the adoptive T-cell
therapy fıeld. CD19 has become the poster child for CAR
therapies. The most remarkable results have been reported
to date in ALL, in both adults and children. Remarkably,
the CR rate remains high irrespective of patients’ age or
prior treatments. sCRS may occur in patients with high
tumor burden, but means to control it are available.
CD19-negative relapse may occur (possibly more commonly
in children), for which CD22 CAR therapy may
provide an effective recourse. 26 CD19 CARs, which received
breakthrough designation by the U.S. Food and
Drug Administration at CHOP and at MSKCC in 2014,
will soon become part of the armamentarium for B cell-
ALL and other B cell malignancies.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: Renier Brentjens, Juno Therapeutics. Michel Sadelain, Juno
Therapeutics. Isabelle Riviere, Juno Therapeutics. Honoraria: None. Consulting or Advisory Role: Renier Brentjens, Juno Therapeutics. Jae Park, Amgen,
Juno Therapeutics. Michel Sadelain, Juno Therapeutics. Isabelle Riviere, Juno Therapeutics. Speakers’ Bureau: None. Research Funding: Renier Brentjens,
Juno Therapeutics. Jae Park, Juno Therapeutics, Genentech/Roche. Isabelle Riviere, Juno Therapeutics (Inst). Patents, Royalties, or Other Intellectual
Property: Renier Brentjens, Scientific Cofounder of Juno Therapeutics. Michel Sadelain, Scientific Co-Founder of Juno Therapeutics. Isabelle Riviere, royalty
sharing agreement. Expert Testimony: None. Travel, Accommodations, Expenses: Isabelle Riviere, Juno Therapeutics. Other Relationships: None.
References
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3. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and
co-inhibition. Nat Rev Immunol. 2013;13:227-242.
4. Maher J, Brentjens RJ, Gunset G, et al. Human T-lymphocyte cytotoxicity
and proliferation directed by a single chimeric TCRzeta /CD28 receptor.
Nat Biotechnol. 2002;20:70-75.
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