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CELL & GENE THERAPY INSIGHTS

ADVANCED CELL THERAPIES –


PROGRESS TOWARDS THE CLINIC

EXPERT INSIGHT

Unlocking the therapeutic and


commercial potential of CAR-T
technology
Michelle J Smith, Brittni M Peterson & Barbara A Nelsen

The striking clinical results of CAR-T therapies in blood cancers have


shifted the cell therapy field from one that has future potential, to one of-
fering hope of a future to those living with cancer. Since 2012 the field has
expanded beyond investigators to investment and initial public offerings,
individual ‘cures’ and industry growth. Here, we review the current state
of CAR-T therapeutics, from improvements in CAR-T technology to clin-
ical results, business growth and future applications. Finally, we discuss
the remaining barriers to successful commercialization of CAR-T technol-
ogy identified by key investors within this rapidly expanding field.
Submitted for review: Aug 2 2016 u Published: Oct 3 2016

The body’s adaptive immune system receptor (CAR) that allows them effective therapeutic tool in treating
provides a powerful and safe way to recognize antigens on malignant certain types of cancers, particu-
to eliminate health threats. Begin- cells. This modification eliminates larly hematological malignancies.
ning with vaccines in the late 1700s the need for other components of The clinical successes achieved by
and moving to the use of antisera, the immune system to present the CAR-T therapies have stimulated
monoclonal antibodies and most antigen to the T cell. In turn, this interest and participation from in-
recently T cells, researchers have streamlines the process of trigger- dustry players. Millions of dollars
sought to harness people’s own im- ing the cytolytic signaling cascade, from private, public and govern-
mune systems to fight their own making these T cells cancer-killing ment sectors have been invested in
diseases. Today, technology has en- machines. the last few years and collaborations
abled the genetic modification of T In the past few years, CAR-T among bio-ventures and academic
cells to express a chimeric antigen cells have proven to be a highly facilities have been initiated. The

www.insights.bio

357
CELL & GENE THERAPY INSIGHTS

increased activity has translated to these companies garnered interest


the optimization of CAR-T con- from the public markets, with ini-
structs at the bench, and the devel- tial public offerings totaling nearly
opment of applications both within $1 billion to date (Figure 1 & Table 2)
and beyond hematological cancers [Nelsen Biomedical Analysis].
at the bedside. However, more im- Big Pharma’s hesitation to engage
provements are required to increase in the cell therapy industry also
the safety and efficacy of these ther- shifted in 2012, with the clinical re-
apeutics and the advance towards sults of CAR-T in ALL and chronic
their commercialization. In this lymphocytic leukemia (CLL). That
article, we review the scientific and year marked the first commercial
clinical evolution of CAR-T cells, partnership in this space, between
their translation into treatments for Novartis and the University of
patients and the commercialization Pennsylvania, USA (Figure 1 & Ta-
barriers that need to be overcome ble 3) [3]. Since 2012, seven other
to unlock the potential of CAR-T Big Pharma companies have placed
therapies. bets in the CAR-T space, totaling
at least $1.5 billion in upfront and
equity payments and over $2 billion
in additional milestone, royalty and
THE BUSINESS OF CAR-T other payments (Figure 1 & Table 3).
THERAPEUTICS It is worth noting, however, that for
The development of CAR-T cells by most Big Pharma companies their
Zelig Eshhar and Steven Rosenberg focus is on allogeneic approaches.
in 1990 was an attempt to improve Carolyn Green, Executive Director
our ability to use the body’s innate of Strategic Investments at Pfiz-
immune system to target and ‘cure’ er, has commented, “Autologous
cancer [1]. More than two decades approaches do not fit the business
later, this approach has reached a model of Pfizer. CAR-T therapy will
tipping point. The striking clinical require very different manufactur-
success achieved in treating acute ing and distribution than tradition-
lymphoblastic leukemia (ALL) in al pharmaceuticals or antibodies –
the case of Emily Whitehead, the which are ‘one-to-many’ therapies.
first pediatric patient to be treat- Pfizer has only one focus on CAR-T
ed with CAR-T therapy in spring and that is the allogeneic approach,
2012, was a game changer. It was where an off-the-shelf product can
this clinical result and the duration be given as a ‘one-to-many’ strate-
of its response that engaged the in- gy. We partnered with Cellectis on
terest of investors, who have con- this.” In the past 2 years, three of
tributed $600 million in venture the top 15 highest valued immu-
capital (VC) to directly support the no-oncology partnerships were Big
development of CAR-T therapeu- Pharma’s investments in CAR-T
tics through August 2016 (Figure 1 therapies [4]. Interestingly, two of
& Table 1) [Nelsen Biomedical Analy- these three partnerships are focused
sis; 2].
The majority of this has been on allogeneic approaches and each
invested since 2012 and dedicated is worth at least twice as much as
to autologous CAR-T approaches. the autologous partnership [4].
Within a few years of gaining com- Aside from the VC and Big
mitments from the VC community, Pharma investment deals discussed

358 DOI: 10.18609/cgti.2016.043


ffFIGURE 1
CAR-T companies: venture investments, initial public offerings and pharmaceutical partnerships.

3000
Initial public offering
Venture capital investment
2500
Big pharma strategic partnership
(with CAR-T company) in upfront payments
Equity 2000
Upfront payment (not specified)
Allogeneic CAR-T approach 1500
Autologous and allogeneic CAR-T approach
*+
$ in millions

$1000 million 1000

+ 500
$100 million
* *
$10 million * * *

2011 2012 2013 2014 2015 2016

Cell & Gene Therapy Insights - ISSN: 2059-7800


Beginning in 2011 with Kite Pharma, venture capitalists have invested in six companies developing CAR-T therapeutics. Total venture capital (VC) dollars have reached over $600 million as of
September 1st 2016 (see Table 1 for details). The six companies funded, the majority of which are developing autologous CAR-T therapies, completed initial public offerings totaling nearly $1
billion (see Table 2 for details). Since the first Big Pharma strategic partnership in the CAR-T space between Novartis and the University of Pennsylvania in 2012, seven other Big Pharma companies
have followed suit, placing bets of at least $1.5 billion in upfront payments, the majority for allogeneic approaches marked by asterisks (see Table 3 for details).
Includes only VC funding for companies involved in CAR-T program(s) at the time of investment. For example, VC funding of Bluebird Bio occurred prior to their CAR-T programs, while the company
had only a gene therapy focus. These investments are not included. See Table 1 for details.
Includes only initial public offerings where the company had a CAR-T focus at the time of going public. See Table 2 for details.
Includes only strategic partnerships where Big Pharma companies invest in and obtain rights to CAR-T therapeutic programs. Not included, for example, is the Roche and Genentech partnership
with Kite Pharma in March 2016 to combine Kite’s CAR-T technology with Roche or Genentech’s small molecules. See Supplementary Table 1 for other deals like this. Payments are upfront only,
see Table 3 for additional details on milestone, royalties and other terms.
Sources: Company press releases, Nelsen Biomedical Analysis.
Expert Insight

359
CELL & GENE THERAPY INSIGHTS

ff TABLE 1
Venture capital investment in CAR-T companies
2011–2016.
Company Venture Date CAR-T
capital ($ in approach
millions)
Kite Pharma 15 Mar 2011 Autologous
Kite Pharma 20 May 2013 Autologous
Kite Pharma 50 Apr 2014 Autologous
Juno 176 Apr 2014 Autologous
Juno 134 Aug 2014 Autologous
Bellicum 55 Aug 2014 Autologous
Autolus 45 Jan 2015 Autologous
Poseida 23 Dec 2015 Allogeneic
CARsgen 30 Jan 2016 Autologous
Autolus 57 Mar 2016 Autologous
Total 605
Includes only venture capital funding for companies involved in CAR-T program(s) at
the time of investment. For example, venture capital funding of Bluebird Bio occurred
prior to their CAR-T programs, while the company had only a gene therapy focus. These
investments are not included.
Source: Company press releases.

above, there have been over 75 ad- outlook it is necessary to examine


ditional partnership, acquisition the scientific evolution of CAR-Ts,
and licensing deals done from 2012 their clinical applications and the
through August 2016 worth at least barriers to commercialization.
another $650 million in disclosed
upfront payments and $2 billion
in additional milestone, royalty and
other payments [Nelsen Biomedi- THE EVOLUTION OF
cal Analysis]. The number of deals CAR-Ts
in this space has grown every year, Monoclonal antibody-based ther-
from just three deals in 2012 to 35 apies achieve anti-tumor activity
in 2015. With already 26 deals as by influencing T cells within the
of September 1, 2016, the full-year patient’s body through cell-intrin-
2016 numbers will likely reach at sic signaling. This is one way to
least the 2015 figure. These deals modify the adaptive immune sys-
cover intellectual property, new tem and target cancer cells. At the
approaches for creating CARs us- National Institutes of Health, USA,
ing gene-editing technologies, ex- Steven Rosenberg took a different
pansion to allogeneic approaches, approach by harvesting, expanding
combination therapies and more and re-infusing tumor-infiltrating
(Supplementary Table 1, nelsenbio- lymphocytes from melanoma pa-
medical.com/cartdeals). tients. While this technique laid the
Overall, the T-cell immunothera- groundwork for future T-cell-based
py market is projected to be worth therapies, it showed limited effica-
$30 billion by 2030, with CAR-T cy. In addition, when the affinity of
therapies likely to garner the most the T-cell receptor (TCR) was in-
attention in the near future [5]. To creased, safety issues emerged [6,7].
understand the true commercial This therapy, like all based on TCRs,

360 DOI: 10.18609/cgti.2016.043


Expert Insight

ff TABLE 2
Initial public offerings of CAR-T companies 2011–2016.
Company $ IPO (in IPO date CAR-T
millions) approach
Bluebird bio 101 Jun 2013 Autologous
Kite 128 Jun 2014 Autologous
Bellicum 140 Dec 2014 Autologous
Juno 265 Dec 2014 Autologous
Cellectis 228 Mar 2015 Allogeneic
Celyad 100 May 2015 Allogeneic and
autologous
Total 962
Only includes IPOs where the company had a CAR-T focus at the time of going public.
IPO: Initial public offering. Source: Company press releases.

was dependent on the presentation one signal of the three required for
of its target antigen in the context activation of T cells [11,12]. As a
of a major histocompatibility mol- result, T cells receiving stimulation
ecule (MHC), which increases the through a first-generation CAR
complexity of engineering the TCR. without accompanying co-stimu-
The development of the CAR-T lation often become anergic. This
cells addressed this shortcoming of negatively impacts the ability of the
TCR-engineered T cells. The CAR cell to function effectively and its
combines the antigen-recognition ability to persist over time.
portion of the B-cell receptor, which These limitations were addressed
functions independently of MHC, by incorporating the signaling do-
with the T-cell intracellular signal- main of a co-stimulatory mole-
ing domain (CD3ζ) [8]. This allows cule into the CAR construct (Fig-
the T cell to recognize any surface ure 2). This iteration created the
molecule to which an antibody can second-generation of CARs. The
be made and results in a highly ef- co-stimulatory domains they include
fective therapeutic tool, even in dis- vary, but are most commonly de-
ease refractory to chemotherapy. rived from CD27, CD28, OX40 or
4-1BB. The inclusion of one of these
First-, second- & third-gen- co-stimulatory domains signifi-
eration CAR-Ts: focus on cantly improves the expansion and
improving effectiveness persistence of CAR-T cells, thereby
In the most basic CAR construct, improving their anti-tumor effect
the functional sections are the vari- [10,13]. Following the success of the
able portion of an antibody that is second-generation of CAR-T tech-
specific for the intended target (scFv nology, more than one co-stimulato-
or antigen recognition), usually a ry molecule was added in the hopes
tumor-associated antigen, and the of achieving an additive or synergis-
CD3ζ [9]. When the scFv binds to tic increase in effectiveness (Figure
its target antigen, the CD3ζ initi- 2). However, this did not prove out,
ates the TCR signaling cascade, thus with the third-generation of CAR-Ts
activating the cytolytic function of showing no improvement in tumor
the CAR-T [10]. The first-genera- clearance. In fact, in the majority
tion CARs (Figure 2) provide only of cases second-generation CAR-Ts

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CELL & GENE THERAPY INSIGHTS

ff TABLE 3
Big Pharma–CAR-T companies strategic partnerships 2011–2016.
Company/ Big Deal type Deal value CAR-T Date
Institution Pharma approach
University of Novartis Exclusive global Not disclosed Autologous Aug
Pennsylvania research and licensing 2012
agreement
Bluebird Bio Celgene Exclusive multiyear Not disclosed Autologous Mar
research and collabo- 2013
ration agreement and
license agreement
Cellectis Servier Collaboration Servier will pay $10 million Allogeneic Feb
upfront and up to $140 million 2014
for each of the 6 product can-
didates potentially developed
Cellectis Pfizer Collaboration Pfizer will pay $80 million Allogeneic Jun
upfront plus up to $185 million 2014
per product and royalties
Transposagen John- Collaboration and Unspecified upfront; Johnson Allogeneic Nov
son and license agreement and Johnson will pay up to 2014
Johnson $292 million per treatment in
milestones
Kite Pharma Amgen Collaboration Amgen to pay $60 million Autologous Jan
upfront and up to $525 million 2015
per product in milestone pay-
ments, plus royalties on sales
and IP licensing
Ziopharm/ Merck Strategic collaboration Merck to pay $115 million Autologous Mar
Intrexon and license agreement upfront, fee will be split equally & allogeneic 2015
between Intrexon and partner
Ziopharm Oncology along with
a commitment of up to $826
million more in milestones for
the first two programs
Bluebird Bio Celgene Collaboration Celgene to pay $25 million Autologous Jun
2015
Juno Celgene Collaboration Celgene to pay approximately Autologous Jun
$1 billion, composed of an 2015
approximately $150 million
upfront payment and approx-
imately $849.8 million to
purchase 9,137,672 shares
of Juno's common stock at
$93.00 per share
Cellectis Servier Exclusive global license Servier to pay $38.2 million Allogeneic Nov
and collaboration upon signature and eligible for 2015
agreement over $300 million of milestone
payments, R&D financing and
royalties
Precision Baxalta Collaboration Baxalta to pay Precision $105 Allogeneic Feb
Biosciences million upfront, followed by up 2016
to $1.6 billion in option fees
and payments milestones and
royalties
Juno Celgene Exercised option Celgene will pay Juno a fee of Autologous Apr
$50 million and the companies 2016
will now share global develop-
ment expenses for products in
the CD19 program
Only includes strategic partnerships where Big Pharma companies invest in and obtain rights to CAR-T therapeutic programs. Not
included, for example, the Roche and Genentech partnership with Kite Pharma in March 2016 to combine Kite’s CAR-T technology with
Roche or Genentech’s small molecules. See Supplementary Table 1 for other deals like this. Payments are upfront only, Source: Company
press releases.

362 DOI: 10.18609/cgti.2016.043


Expert Insight

have achieved better outcomes [14] CD19-expressing ALL than in other


and these, but not third-generation applications [15–18]. Reduced effica-
CAR-Ts, have proceeded into clini- cy in some applications is due in part
cal trials. to suppressive effects that the tumor
has on the CAR-T engineered cells.
Next-generation CARs: to And these suppressive effects of the
overcome suppression & tumor microenvironment are more
improve safety pronounced in solid tumors than
While second-generation CARs in hematopoietic tumors. With the
have achieved some significant pre- aim of correcting this suppressive
clinical and clinical successes, more effect, a new generation of CAR-T
improvements in safety and efficacy referred to as TRUCKs, deliver a
are needed. For example, even in ‘payload’ of immune-activating
the most successful CAR-T target to chemokines or cytokines (Figure 2).
date, anti-CD19 CAR-T therapies, This enhances the effectiveness of the
responses are variable. These thera- CAR-T through recruitment of ad-
peutics are more effective in treating ditional immune cells to the tumor

ffFIGURE 2
The evolution of chimeric antigen receptors.

Generation 1st 2nd 3rd 4th

Modification goal Improve Increase TRUCK: manipulate Switchable: increase


persistence effectiveness microenvironment control (safety)

Extracellular scFv
domain (tumor
antigen biniding)

Co-stimulatory domain Bifunctional switch CD3ζ


Co-stimulatory domain Cas9 Drug binding inducible
Cytokine Cas9 switch

The first-generation CARs include CD3ζ, one of the three signals required for the activation of T cells. Second-generation CARs
incorporate a second, co-stimulatory signaling domain to improve the persistence of CAR-T cells. In third-generation CARs, more
than one co-stimulatory molecule was added, but a resultant increase in effectiveness has yet to be conclusively proven. There are
several different iterations considered to be fourth generation. One of which are TRUCKs that deliver immune activating chemokines
or cytokines to manipulate the microenvironment. The other two are switchable CARs that can be regulated by a bi-functional antibody
to control activation or by small molecules that can induce apoptosis, both of which are aimed at increasing safety.
Sources: [9,10,13,20,22,23,24].

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microenvironment and increased tu- therapies have grown in tandem


mor killing via both these additional with cellular immunotherapy, com-
cells and the inflammatory cytokines prising 50% of all new cellular
themselves [19,20]. immunotherapy clinical trials and
25% of total cell therapy clinical
Regulatable CARs focus on trials overall (Figure 3A) [Nelsen Bio-
improved safety medical Analysis]. Growth has oc-
Many patients, approximately 55%, curred in both the total number of
experience side effects related to cy- new trials started each year and also
tokine release as a result of CAR-T progression to later stages (Figure
therapy [21]. Cytokine release syn- 3B). As of September 1, 2016, the
drome side effects are often mild, number of new CAR-T cell therapy
flu-like symptoms but can be severe, trials initiated has already surpassed
including hypotension, vascular the 2015 figure (Figure 3B) [Nelsen
leak, pulmonary edema and coagu- Biomedical Analysis].
lopathy, leading to multi-organ fail-
ure and even death. Currently these Blood cancers
complications are managed with CAR-T cells have shown extraordi-
corticosteroids and anti-IL-6 therapy nary success in treating B-cell hema-
[15]. Investigators are experimenting tologic malignancies such as ALL,
with incorporating elements into CLL and non-hodgkins lymphoma
new CAR designs to allow them to (NHL). Depending on the specific
be regulated, with the aim of increas- trial and indication targeted, overall
ing the safety of these therapies. Ex- response rates typically range from
amples of recently developed safety 40 to 94% [21]. Collectively, recent
measures include switchable CAR-T trials in patients with ALL, CLL or
whose activity can be modulated by NHL show that on average 75%
small molecules, and the inclusion of of patients experience a complete
an inducible caspase 9 to allow di- or partial response, with a majority
rected apoptosis of the CAR-T (Fig- (67%) showing a complete response
ure 2) [22,23]. Additional approaches [21].
continue to be developed with the Of these three blood cancers, the
hope of improving safety through al- results in patients with refractory or
ternatives such as antibody-coupled relapsed ALL have been the most im-
T-cell receptor technology, in which pressive. Most people have heard of
the receptor on the T cell must be ac- the poster child of this game changer
tivated by a separately administered in the fight against this deadly dis-
antibody and in this way titration of ease, Emily Whitehead whose last
response can be achieved. ditch treatment by Dr Porter at the
University of Pennsylvania has left
the now 11-year-old cancer free for
over 4 years. Since then, ALL pa-
CLINICAL APPLICATIONS tients treated with CAR-T therapies
The optimization of CAR-T con- targeting CD19 exhibit complete
structs at the bench has translated response rates of approximately 90%
not only to the success of these ther- [24], a remarkable improvement over
apies in ALL, but also to the expan- other existing therapies for ALL,
sion of CAR-T clinical trials. From such as chemotherapy and allo-stem
2011 to 2015, trials using CAR-T cell transplant (SCT) where response

364 DOI: 10.18609/cgti.2016.043


Expert Insight

rates and durable remissions are Other CAR-T therapies target-


<50% [25]. Notably, this 90% com- ing CD19 to treat B-cell hemato-
plete response success rate has been logic malignancies are equally im-
observed across all age groups, from pressive compared to response rates
pediatric to adult populations, and with current therapeutics. However,
across independent trials taking in comparison with ALL, CLL and
place at different academic medical NHL have yielded more variable
facilities [21,24,25]. The consistency response rates – between 40 and
in these successful outcomes in blood 85% overall response and 20 and
cancers is particularly profound, giv- 60% complete response [21,25].
en that inconsistencies tend to arise While ongoing research is focused
due to the variety of protocols, in- on understanding how to achieve
frastructure and clinical staff used more effective and consistent re-
across the clinical trials. sults using CAR-Ts for CLL and

ffFIGURE 3
CAR-T clinical trials.

A 2011 2015

Immune
31% Immune
48%
CAR-T
Other 15% Other
69% 52%

CAR-T
24%

B 70
Projected to
60 Phase 1 12/31/2016
Phase 1/Phase 2
50 Phase 3

40 09/01/2016

30

20

10

0
2007 2009 2010 2011 2012 2013 2014 2015 2016

(A) CAR-T clinical trials as a percent of all cell therapy trials. From 2011 to 2015, trials using CAR-T therapies have grown in tandem
with cellular immunotherapy, comprising 50% of all new cellular immunotherapy clinical trials and 25% of total cell therapy clinical trials
overall. (B) Since 2007 the number of new CAR-T therapy trials started each year has climbed dramatically. With the total already at 41
as of September 1 2016, this number could reach nearly 70 by the end of the 2016 calendar year. Increases in overall numbers of CAR-T
trials are matched by progression through phases of development from Phase 1 to Phase 2.
Source: Nelsen Biomedical Analysis.

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NHL, nevertheless this therapeutic that they work for B-cell lympho-
approach for these malignancies mas really well, but there's going
appears to be more promising than to need to be a suite of technical
those that are currently available. alterations for it to work in various
other applications.” (Ben Auspitz,
Expansion to solid tumors F-Prime Capital) Some barriers to
Driven by the success of the CD19- success in solid tumors that need
CAR in treating ALL, CLL and to be addressed through more re-
NHL, CARs specific for other search and technical improvements
cell-surface markers are being ex- include:
plored for the treatment of many dif-
ferent types of malignancies. While ff Identification of safe and
effective antigenic targets for
some target hematologic malignan- each tumor type
cies, such as the anti-CD38 CAR
ff fficient localization of CAR-T
E
[26–28], others are focused on solid cells within the tumor
tumors. Examples include T cells ex- ff eutralization of the
N
pressing CARs specific for IL-11Rα immuno­­suppressive tumor
and variants of CD44, which are tar- microenvironment
geted for head and neck, pancreatic, Research to address these barri-
gastric, breast, cervical and colon ers is ongoing and varies by tumor
cancers [29–31], or a CSPG4–CAR, type, currently ranging from early
which targets melanoma, triple-neg- pre-clinical studies to clinical trials.
ative breast cancer, glioblastoma As we discussed earlier, many anti-
multiforme, mesothelioma, head genic targets are under investigation
and neck cancers, and osteosarcomas to expand CAR-T applications to
[32–34]. Clinical trials are ongoing other blood cancers and solid tu-
for the treatment of neuroblastomas mors. But most of these antigens
and osteosarcomas with a GD2- are expressed on a variety of normal
CAR-T therapy [35]. For neuroblas- cell types. In solid tumors, targeting
toma, early results look promising CARs to overexpressed antigens can
for the only program beyond blood lead to the destruction of healthy
cancers that has progressed to Phase solid organ tissue, such as in the case
2 clinical trials (NCT02765243) of the off target-mediated mortality
[35]. Additional antigens are being seen in HER2 CAR-T therapy for
tested preclinically for targeting solid colon cancer [39]. So, clearly, safety
tumors. Brain cancers, CNS cancers, is a concern and solid tumor-asso-
gliomas, glioblastoma multiforme, ciated antigens must be carefully
and head and neck cancers are being selected. A variety of approaches for
targeted with an ErbB2-CAR-T cell optimizing CAR-T therapy for solid
[36]. Breast cancer responsiveness to tumors range from directly adminis-
CAR-T therapy is being explored tering CAR-T cells to the tumor, to
using c-MET and carcinoembryon- combining CAR-T with small mole-
ic antigen (CEA) CAR-T cells [37], cules that regulate cytokine and sur-
while prostate cancers are being tar- face receptor responses, to transient
geted with a prostate-specific mem- CAR expression. These strategies
brane antigen CAR-T construct [38]. are thoroughly summarized in two
What’s the real potential for recent reviews in Molecular Therapy
CAR-T in cancers beyond blood? – Oncolytics [40] and the Journal of
One investor noted that: “We know Cytotherapy [41].

366 DOI: 10.18609/cgti.2016.043


Expert Insight

CAR-T therapies beyond widespread adoption and produc-


cancer tion of CAR-T therapy.
Further on the horizon, research-
Technical challenges
ers have begun work to adapt CAR
technology for the treatment of au- Technically, some areas requiring
toimmune diseases. For these ap- additional work include:
plications the CAR is engineered to ff Identification of safe and
be reactive against self-antigens, but effective antigenic targets for a
variety of tumor types
instead of being attached to a con-
ventional T cell, it is attached to a ff ptimizing CAR design for
O
maximum efficacy
regulatory T cell (Treg). In this way,
it is hoped that tolerance against spe- ff I nclusion of appropriate safety
controls into CAR design
cific self-antigens can be achieved.
This method has achieved some pre- These topics have already been
clinical successes in mouse models of discussed above. Briefly, to the first
colitis and multiple sclerosis. CAR- point, identifying tumor-specific
Tregs for the treatment of colitis antigens (not expressed by normal
have been generated against multi- cells) will be key to avoiding on-tar-
ple targets (2,4,6-trinitrophenol and get, off-tumor effects. However, even
CEA); both have shown specificity, with effective antigens to direct CARs
improvement in survival and ame- against, the tumor can down-regulate
lioration of inflammation-associated the antigen (antigenic escape), which
symptoms [42,43]. In the treatment can be detrimental to therapeutic ef-
of experimental autoimmune en- ficacy. The prevailing approach to
cephalomyelitis, which is a mouse combatting antigenic escape is to tar-
model for multiple sclerosis, the get multiple antigens on the tumor,
CAR used was directed against my- such as using CD22-CAR-T cells
elin oligodendrocyte glycoprotein to treat patients who have relapsed
and produced a durable reduction in with CD19-negative ALL following
symptoms, even in the face of a sec- successful CD19-CAR-T therapy
ond induction of disease [44]. (clinical trials NCT02650414 and
Clearly, CAR-T technology holds NCT02315612).
promise in a variety of therapeutic Often overlooked, but equally
areas when and where the highly important to efficacy is how the cell
specific nature of its antigen target- therapy product is manufactured. Re-
ing can be leveraged. However, in- cent work has shown that “the meth-
vestors we spoke with said that only od used for expanding T cells prior to
when additional antigens can be spe- infusion is an essential determinant of
cifically targeted and show efficacy their in vivo efficacy” [45]. Companies
similar to that achieved with CD19 need to give serious considerations to
and B-cell lymphoma, will the field the way in which CAR-T cells are
beyond blood cancers take off. generated, as this can have significant
impacts on efficacy. With manufac-
turing, enrichment of the ‘active in-
gredient’ may be achieved through a
CHALLENGES FOR CAR-T combination of:
There remain technical, clini- ff I mproved protocols for
cal and commercial challenges transduction efficiency and cell
that must be overcome for the selection

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ff Optimizing in vitro growth (see the second column in Table 4)


conditions to enhance outgrowth [46]. In a third Phase I clinical trial
of the desired cell population
for B-NHL, CAR-T cells produced
ff Enrichment of the ‘active from a central memory cell popu-
ingredient’
lation using a more complex proto-
The effectiveness of CAR-T ther- col achieved an 88% response rate.
apy may reasonably be expected to This was an improvement on a sim-
depend on the percentage of cells ilar simpler protocol that utilized a
expressing the CAR of interest. In bulk T-cell starting population and
fact, comparing three different pro- resulted in only a 74% response
tocols for manufacturing CD19- rate for B-ALL, which traditional-
CAR-T cells for clinical trials in ly is the most responsive to CD19
ALL demonstrates the significant CAR-T therapy (see column 3 in
impact that the transduction effi- Table 4) [47,48]. Through these and
ciency can make in the results. Cells other examples, the importance of
produced with one manufacturing optimizing transduction efficien-
protocol (see the first column in Ta- cy during manufacturing is clear.
ble 4) [45] did not yield any respons- Accordingly, clinical protocols that
es during a Phase 1 clinical trial. do not include enrichment for cells
Modifying both the vector and the expressing the target CAR may re-
transduction and expansion steps in quire higher initial transduction
a different manufacturing protocol efficiencies. In addition, shifting
improved efficacy significantly, giv- manufacturing processes to opti-
ing a clinical response rate of 74% mize the input population of T cells

ff TABLE 4
Comparison of selected CAR-T manufacturing protocols.
Protocol 1 Protocol 2 Protocol 3

CD19+ ALL and


Cancer Type CD19+ ALL CD19+ NHL
CLL
Pediatric and Adult
Patient Population Adult
Young Adult
Step 1 Cell Enrichment All T cells All T cells Memory T Cells

Spinnoculation Retronectin (No Spinnoculation


Step 2 Transduction
with Retronectin Spinnoculation) with Retronectin

Step 3 Growth Factors IL-2 IL-2 IL-2, IL-15


Step 4 Initial Expansion Step Yes Yes Yes
Stimulation Bead
Step 5 Yes Yes Yes
Removal
Step 6 Second Expansion Step No Yes Yes
MSGV
Vector SFG (Retrovirus) HIV (Lentivirus)
(Retrovirus)
% CAR Expression/
14–40% 50–80% 60–90%
Product
Total Cell Fold
100–700x 10x 600x
Expansion
Total Time Required 2–3 weeks 1–2 weeks 3–6 weeks
Clinical Results NR 74% RR 88% RR

368 DOI: 10.18609/cgti.2016.043


Expert Insight

with memory subsets, which have careful monitoring and modifica-


shown increased effectiveness [49], tion of oxygen and glucose levels
may further improve success rates. throughout manufacturing.

Optimizing growth Clinical challenges


conditions in vitro to Clinical challenges also pose a bar-
improve results in vivo rier to the successful commercial-
A second area of focus should be ization of CAR-T. Three areas of
the specific media, cytokines and particular concern outlined by in-
atmospheric conditions provided vestors we interviewed include:
during manufacturing. Small per-
ff efining and predicting potency
D
turbations in these conditions can of the active ingredient
strongly influence the outgrowth
ff tandardization of practices
S
of subpopulations within a het- across multiple clinical sites
erogeneous input population. Op-
ff Developing clinical infrastructure
timizing the culture conditions to
produce the required population First, defining minimum poten-
through pre-culture enrichment cy standards is needed. Currently,
protocols and control of media a dose is defined as a number of
and atmospheric conditions will cells administered. But a cell thera-
be an advantage in the production py dose consists of a heterogeneous
of adoptive cell therapies. Consid- mix of cells. As we discussed, selec-
er, for example, differing effects tion of T-cell populations and ef-
that co-stimulatory molecules ficient CAR transduction to these
may have on the metabolic needs cells can significantly affect the po-
of CAR-T cells. If the co-stimu- tency of the cell product. However,
latory molecule is CD28, the cell as we are still defining important
is pushed towards glycolysis and characterizations of these cellular
will require higher glucose levels. therapeutics, qualitative standards
If the co-stimulatory molecule is defining requirements to obtain
4-1BB, the cell is pushed towards minimum clinical efficacy have not
oxidative phosphorylation and yet been established. Until then,
will require higher oxygen levels demonstrating clinical equivalency
[50]. These are important con- when each batch is patient specific
siderations for both therapeutic (n = 1) remains a significant chal-
design and manufacturing. Ox- lenge to success in clinical trials,
idative phosphorylation is more regulatory approval and production
energetically efficient, so, for a he- on a commercial scale.
matopoietic target, 4-1BB may be Second, clinical practices must
the obvious choice for co-stimula- also be standardized, such as the es-
tory molecule. However, for solid tablishment of preparative regimens
tumors existing in a hypoxic mi- and treatments for adverse events.
croenvironment, relying more on The importance of preparative regi-
glycolysis through CD28 could mens has recently been underscored
be an advantage as it reduces the by the deaths in Juno’s clinical trial
requirement for oxygen. When for ALL using JCAR015. A balance
manufacturing these cells, yields must be struck in providing the cor-
of therapeutically effective CAR- rect lympho-depleted environment
Ts may be improved through without causing adverse effects.

Cell & Gene Therapy Insights - ISSN: 2059-7800 369


CELL & GENE THERAPY INSIGHTS

Lastly, the clinical infrastructure facilities [Nelsen Biomedical Inter-


is needed to scale from single sites, views]. This is an obstacle for those
where the majority of clinical tri- working to commercialize CAR-T
als are currently conducted, to the therapy, and for investigators work-
multiple sites necessary for success- ing on new approaches.
ful commercialization of these ther- Cost of goods is an additional
apies. Clinical trials now are typical- barrier that has been widely dis-
ly performed at a single center with cussed [51–55]. The first FDA-ap-
deep medical expertise. We need proved dendritic cell (DC) thera-
the clinical infrastructure, expertise py, Provenge®, was developed by
and standardization to scale from Dendreon. DCs stimulate anti-
one clinical site to many. Otherwise gen-specific cytolytic and helper
these therapies will not be success- T-cell responses, which lead to the
ful in reaching larger patient popu- formation of immunological mem-
lations and markets. ory. This capability has been used
as a strategy to develop autologous
Commercial challenges cancer vaccines. Despite the effi-
To gain perspective on the biggest cacy of Provenge, the commercial
barriers to the expansion of com- challenges posed by manufactur-
mercial opportunities for CAR-T ing resulted in Dendreon filing for
therapies, we interviewed VC firms bankruptcy. How then, can com-
who actively invest in this space. panies attempting to commercial-
While multiple areas for improve- ize autologous CAR-T therapies
ment were discussed, three key areas avoid the same fate?
of focus emerged including: Fortunately, the industry has
ff Availability of Good
been working on developing more
Manufacturing Practice (GMP) efficient and cost-effective solu-
facilities tions for manufacturing thera-
ff Reduction in the cost of goods pies where small-scale is full-scale.
sold Shifts to disposable, small-foot-
ff pplication to bigger market
A print solutions as well as semi- or
opportunities fully-automated, entirely enclosed
"Producing autologous CAR-T manufacturing systems can re-
cells requires at least two unique duce costs due to personnel, clean
types of facilities/processes. First, a rooms and consumables. Notably,
virus manufacturer to produce ret- some of these automated, enclosed
ro- or lentivirus to modify the cells, ‘plug-and-play’ systems in devel-
and then also a cell manufacturing opment may ultimately be able
facility to process the patients' cells, to manufacture cells from up to
transduce them with the virus, and 30 donors in parallel. Putting this
then expand, characterize and for- into perspective, one CEO of a cell
mulate them. Currently both types therapy Contract Manufacturing
of facilities have long wait lists and Organization (CMO) noted that
additional ramp up is needed to scale “many of our clients' clinical pro-
supply." (Michael Gladstone, Atlas grams are such that if they're suc-
Ventures). This 18-month waitlist cessful they will need to increase
exits both at commercial manu- their current use from one to ten
facturing sites as well as academic clean rooms a month, to 100 clean
and institutional manufacturing rooms a month. That's simply not

370 DOI: 10.18609/cgti.2016.043


Expert Insight

feasible. The concept of having a of partnerships being executed to


fully enclosed system that could focus on manufacturing (Figure 4).
process in parallel 30 patients at a In fact, despite the stage of devel-
time is very appealing.” (M Bam- opment, companies have begun to
forth, Brammer Bio). At least ten invest in automated manufactur-
closed manufacturing options are ing solutions. For example, with
in development or on the market, CAR-T therapy in just their pre-
with more improvements on the clinical pipeline, GlaxoSmithKline
way [56]. The need to incorporate has recently entered into an agree-
effective manufacturing has clearly ment with Miltenyi Biotec to auto-
been recognized by companies in mate manufacturing and overcome
the field, with increasing numbers scale-up constraints. In addition,

ffFIGURE 4
CAR-T therapeutics company deals by focus.

18
Combination therapy for liquid tumors
16
Combination therapy for solid tumors
Solid tumor
14
Manufacturing
Gene editing technology
12
Number of Deals

10

0
2012 2013 2014 2015 2016

As gene editing is integral to the CAR-T platform, companies began to form strategic partnerships to access or to license gene editing
technology in 2012. The number of gene editing deals peaked in 2014 and has since been on the decline. Access to GMP facilities
and cost of goods sold are significant commercial challenges to the manufacture of CAR-T therapies. Beginning in 2014, companies
developing CAR-T therapies have formed strategic partnerships with GMP manufacturing facilities and companies providing efficient
and cost-effective manufacturing solutions. Since then the number of manufacturing deals has been steadily increasing. Many believe
that therapeutic success of CAR-T in treating solid tumors is critical to commercial success. In 2013, companies developing CAR-T
therapies began forming partnerships and licensing agreements for acquisitions of technologies to develop CARs to treat solid tumors.
The majority of these deals were made in 2015. One strategy to improve efficacy of CAR-T therapies is to combine them with a small
molecule such as an antibody, checkpoint inhibitor or other signaling molecule. Since 2015 there has been an increase in the number
of deals made for developing combination therapies for treating both solid and liquid tumors. See Supplementary Table 1 for additional
details.
Sources: Company press releases and Nelsen Biomedical Analysis.

Cell & Gene Therapy Insights - ISSN: 2059-7800 371


CELL & GENE THERAPY INSIGHTS

the later clinical stage CAR-T Application to bigger market op-


company, Juno, has acquired Cell portunities is the third point cited
Stage Therapeutics, in part for their by investors as a significant chal-
next-generation automated manu- lenge for CAR-T therapies. Accord-
facturing technologies in addition ing to an experienced investor in
to their cell selection and activation this field, “most believe growth in
capabilities (Supplementary Table 1, the industry will stem from success-
nelsenbiomedical.com/cartdeals). es in solid tumors and that if we can’t
Of course, to avoid this issue of figure solid out the CAR-T indus-
scale out, on solution is to develop try will stall”. While we are likely to
allogeneic approaches, which are fa- see registration of CAR-T products
vored by Big Pharma (Table 3). There for blood cancers such as ALL and
were encouraging clinical results NHL in the next few years, CAR-T
from the first patient treated with for solid tumors is a long way be-
Cellectis ‘off-the-shelf ’ CAR-Ts hind. A variety of approaches are
[58–60]. It’s also worth noting that underway in an attempt to translate
recently both Juno and Kite have the successes of CAR-T therapies in
made investments in developing treating hematologic malignancies
off-the-shelf allogenic approaches to solid tumors, as discussed above.
(Supplementary Table 1, nelsenbio- But it is worth noting again that the
medical.com/cartdeals). industry and clinicians will always

ffFIGURE 5
The rise (and fall?) of CAR-T.

2011 2016
Visibility/
expectations
Juno halts clinical trial after 3 deaths (July 2016)
IPOs: Cellectis, Kite,
Juno, Celyad, Bellicum
Novartis closes cell therapy
business (September 2016)
VCs fund: Cellectis, Juno, Celyad
Bellicum, CARsGen, Autolus

First IPO: Blubird (June 2013)

CAR-T success in ALL


(E Whitehead; May 2012)
First Big Pharma
VCs fund: Kite (2011) deal: Novartis-UPenn
(August 2012)
CAR-T success in CLL
(UPenn; August 2011) Trigger Peak of inflated Trough of Slope of Plateau of
expectations disillusionment enlightenment productivity

Technology maturation stages


(time/maturity)

Clinical successes using CAR-T therapies to treat patients with CLL in August 2011 and to treat Emily Whitehead with ALL in May 2012
triggered the excitement in CAR-T cellular therapeutics. Soon after came many firsts in the cell therapy industry. The first Big Pharma
strategic partnership between Novartis and UPenn in 2012, followed by first VC funding to Kite in 2013 and the first IPOs of Bluebird
Bio in 2013. Through 2016, other CAR-T therapeutics companies have raised VC dollars and completed IPOs (Figure 1 and Tables
1 & 2). With the recent deaths of three ALL patients during Juno’s Phase 2 CAR-T clinical trial and Novartis’ announcement that it is
closing down its cell and gene therapy unit, will the industry adjust expectations and enter ‘the trough of disillusionment’?
ALL: Acute lymphoblastic leukemia, CLL: Chronic lymphocytic leukemia, IPO: Initial public offerings, VC: Venture capital.
Sources: [61–64].

372 DOI: 10.18609/cgti.2016.043


Expert Insight

adopt the simplest, safest solution Where are we now? The excite-
that is effective. For solid tumors ment in CAR-Ts has perhaps hit its
there are many approved therapeu- peak until the additional technology,
tics and more in development, from clinical and commercial infrastruc-
small molecules to monoclonal an- ture required matures (Figure 5).
tibodies to combination therapies Fortunately, the past few years have
that provide some level of efficacy. seen increased activity and develop-
A complicated, expensive cell thera- ment of the supporting services and
peutic will only be adopted if it pro- infrastructure needed for the entire
vides a significant improvement in cell therapy industry to move for-
clinical outcome compared to other ward. Manufacturing solutions and
options. services designed to reduce the cost
A quick look at recent deal types of goods, clinical infrastructure and
highlights the main challenges the development of standard operating
industry is trying to address, from procedures to improve safety, effica-
manufacturing, to easier CAR cre- cy and availability of treatment are
ation using gene editing, to im- just a few of the areas where invest-
proving efficacy with combination ment and improvements are occur-
therapies (Figure 4). A more com- ring. Simpler, cheaper methods for
prehensive view of the details of genetic modification for a variety
these recent deals can be found in of cells will also help to move the
Supplementary Table 1 nelsenbio- field forward. Comments Michael
medical.com/cartdeals. Gladstone of Atlas Ventures “If the
[clinical and manufacturing] infra-
structure can be built, it will lay the
groundwork now for a better and
MOVING THE NEEDLE FOR more potent generation of thera-
CELL THERAPY pies.” Beyond just advancing CAR-T
The significant, startling successes of therapeutics, “CAR-T therapy is also
CAR-T therapies in patient popula- paving the way for development of
tions with no therapeutic solution other potentially effective cell thera-
have provided the evidence needed py, including TILs, NK cells and γδ
for the cell therapy industry to gain T cells.” (Shelly Chu, Abingworth).
interest from investors, the public The advancement of even a single
markets and Big Pharma. How- CAR-T therapy for a small patient
ever, the recent deaths in the Juno population all the way to FDA ap-
trial for ALL using JCAR015, and proval will set a precedent that clears
the exit of Novartis from the cell the way for the proliferation, adop-
therapy industry, force us to revisit tion and commercialization of addi-
the practical and clinical realities of tional cell therapies.
these types of therapies for broader
market applications and adoption. FINANCIAL & COMPETING
Right now, everything about them INTERESTS DISCLOSURE
is unwieldy, from collecting the ini- The authors have no relevant financial
tial donor material, to manufactur- involvement with an organization or
ing individual batches of autologous entity with a financial interest in or
cellular therapeutics, to developing financial conflict with the subject matter
pre-conditioning regimens. or materials discussed in the manuscript.
This includes employment, consultancies,

Cell & Gene Therapy Insights - ISSN: 2059-7800 373


CELL & GENE THERAPY INSIGHTS

honoraria, stock options or ownership, This article was written with hope and
expert testimony, grants or patents received anticipation for this future of curative
or pending, or royalties. No writing solutions, and in memory of all those who
assistance was utilized in the production have struggled waiting for this new age
of this manuscript. of cancer medicine, particularly William
and Gloria Nelsen.

ACKNOWLEDGMENTS
The authors would like to thank Ben Aus-
pitz of F-prime, Michael Gladstone of This work is licensed under

Atlas Ventures, Shelly Chu of Abingworth a Creative Commons Attri-

and Carolyn Green of Pfizer for sharing bution – NonCommercial – NoDerivatives 4.0

their time and insights. International License

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376 DOI: 10.18609/cgti.2016.043