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EXPERT INSIGHT
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
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
+ 500
$100 million
* *
$10 million * * *
359
CELL & GENE THERAPY INSIGHTS
ff TABLE 1
Venture capital investment in CAR-T companies
2011–2016.
Company Venture Date CAR-T
capital ($ 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.
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
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.
ffFIGURE 2
The evolution of chimeric antigen receptors.
Extracellular scFv
domain (tumor
antigen biniding)
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].
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.
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].
ff TABLE 4
Comparison of selected CAR-T manufacturing protocols.
Protocol 1 Protocol 2 Protocol 3
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.
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
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].
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,
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
and Carolyn Green of Pfizer for sharing bution – NonCommercial – NoDerivatives 4.0
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