2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond - White Paper
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2021 Outlook for Cell-Based
Therapies in Oncology:
CAR-T Expansion and Beyond
Authored by Jeron Eaves and Pankaj Oza
White Paper
Blue Matter, Copyright © 2021
White Paper
2021 Outlook for Cell-Based Therapies in
Oncology: CAR-T Expansion and Beyond
One year ago when we published an in-depth review of the cell-based immunotherapy landscape,
no one could have predicted the global COVID-19 pandemic and its associated disruptions. But
researchers, drug developers, regulatory agencies, clinicians, and patients all worked hard to ensure
that the cell therapy field continued to advance and deliver promising new treatments in oncology.
Notably, many of the pre-2020 top-of-mind key questions about both commercial success and
scientific potential have now been answered - some of them in surprising ways.
Here, we will:
• Briefly align on the core design • BCMA CAR-Ts: which (class • Other Cell Therapies: (When) will
elements and open questions of) therapy will take the prize in NK Cells and new DC Vaccines
surrounding cell-based therapies in multiple myeloma? succeed in clinic?
oncology: • What’s Next for CAR-T Cell • Review major research, regulatory,
• Overview: What has changed for Therapies: Other targets, and commercial progress during
cell therapies in 2020? technology advances, solid 2020 that has addressed or begun
• CD19 CAR-Ts: Competition heats tumors? to address these key questions
up between the autologous • Non-CAR-T Cell Therapy (TCR-T, • Outline the key milestones for 2021-
players - can allogeneic and next- TILs, etc) - will we see approval(s) 22 that will further address these
gen designs displace? in 2021-22? questions
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White Paper 2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond Overview: What has changed for cell therapies in 2020? Cell therapy design requires please see our previous report here. impacts of COVID-19 on individual selection(s) from each column of In addition to various clinical and cancer patients and health care the elements below, chosen to regulatory developments regarding providers, the pandemic also impacted complement and supplement each these design decisions and attributes several anticipated 2020 milestones other’s attributes. In addition, cell (discussed further below), 2020 also across the cell therapy landscape. therapy development programs must brought a major external disruption Most notably, the FDA cited COVID-19 also define the target (where relevant) to cell therapy development and as a reason for manufacturing and indication(s) for clinical trials. For commercialization, namely, the inspection delays that made liso-cel a deeper dive on these elements and COVID-19 pandemic and its associated miss its end of year approval target, associated design considerations, crises. In addition to the incalculable therefore losing out on a major 3 Blue Matter, Copyright © 2021
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2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
milestone payout. In addition, various well-understood safety / tolerability the established autologous CAR-T
clinical trials experienced pauses and profile, there is always room for design are at the forefront lately,
delays in enrollment, which will no improvement in the overall product particularly the question of autologous
doubt impact data release timelines in profile. This includes efficacy, vs allogeneic cell source. Autologous
the future. safety, and—crucially for these CAR-T manufacturing is inherently
At the beginning of 2021, the complex therapies—speed and time-consuming and expensive, as
cell therapy market is dominated ease of manufacturing and delivery it requires T cells to be successfully
by Novartis’ KYMRIAH and Gilead’s to the patient. Separately, there is obtained from each individual patient,
YESCARTA and TECARTUS which enormous opportunity if cell therapies then purified, modified, expanded, and
share many design commonalities. can succeed in other targets and infused back into the patient.
They have the same CD19 target and indications. This extends beyond Allogeneic CAR-T manufacturing,
despite different order of approvals BCMA in multiple myeloma (where on the other hand, begins with source
they now have overlapping indications we expect one or more CAR-Ts to be cells from a donor or iPSC (induced-
in leukemia/lymphoma, and they approved in 2021), perhaps to include pluripotent stem cell)-generated
are all autologous, costimulatory- solid tumors too, where the TCR-Ts pool, and can therefore skip ahead
boosted CAR-T cells generated using and TILs could be approved within to the modification step. While faster
viral vectors. While we can now rest 2021-2022. and cheaper to produce, it has been
assured that these particular design Several of these design decisions unclear whether these cells would
elements have proven efficacy and a or possible improvements from be as efficacious as patient-derived
KEY 2020-2021 MILESTONES & IMPLICATIONS EOY 2020 Status 2021 Milestones
BMS / Celgene’s liso-cel FDA approval decision (DLBCL) - Safety / tolerability profile DELAYED
(Filed in Feb, but FDA awaiting FDA decision
appears superior; could disrupt YESCARTA and KYMRIAH in DLBCL delayed)
Gilead / Kite’s TECARTUS (KTE-X19) FDA and EMA approval decision (MCL) - First DONE Ph2 data / planned filing
(FDA: Sept,
approval in MCL specifically; pivotal trials in ALL where it could compete with KYMRIAH in Adult-ALL
EU: Dec)
iNHL/FL approvals: Gilead’s YESCARTA FDA approval (indolent NHL); KYMRIAH Ph2 data / YESCARTA awaiting FDA
CD19 ON TRACK decision (KYMRIAH
CAR-T filing planned for 1H21 - competition in FL (Filed: Sept)
planned filing 1H21)
DLBCL earlier lines: YESCARTA Ph3 data / filing in 2L DLBCL; KYMRIAH Ph3 data / filing in ON TRACK YESCARTA (2021)
1L DLBCL - what will be eventual standard of care when to use CAR-T? (Data: Dec) KYMRIAH (2H21)
Allogeneic CD19 CAR-T Ph1 data: Precision Biosciences’ PBCAR0191 (NHL, B-ALL),
Allogene / Cellectis / Servier’s ALLO-501(A) (NHL), CRISPR’s CTX110 (B Cell Malignancies) - ON TRACK mature datasets expected
(initial Ph1 data: Q3)
Will enable comparisons to autologous
BMS / Celgene’s ide-cel updated FDA approval decision (MM) - could be first non-CD-19 DELAYED awaiting FDA decision
(filed in Jul; initially
CAR-T approval; would hint at success of other earlier stage BCMA CAR-T after re-filing
rejected, re-filed Sept)
Janssen’s cilta-cel (JNJ-4528) FDA approval decision (MM) - Would compete with ide-cel ON TRACK awaiting FDA decision
BCMA (Filed: Dec)
CAR-T Allogeneic BCMA CAR-T Ph1 data: Allogene / Cellectis’ ALLO-715 initial Ph1 data and ON TRACK mature datasets
Celyad’s CYAD0202 initial Ph1 data - first allogeneic data to compare to autologous (initial data: Dec)
BCMA competition: GSK’s ADC Blenrep (belantamab mafodotin) FDA approval DONE market competition once
(Approved: Aug) CAR-T launch
Other targets Ph1 data: Celyad’s NKG2D portfolio, Precigen’s MUC16 and CD33, Bellicum’s ON TRACK mature datasets
PSCA and HER2, Cellectis’ UCART platform (CS1/SLAM7, CD22, CD123) (initial data)
CAR-T Non-viral-transduced Ph1 data: CRISPR (CRISPR, Fate), ARCUS (Precision Biosciences), ON TRACK mature datasets
“Next Gen” Sleeping Beauty (Precigen, Ziopharm) (initial data)
Switches and other Mods Ph1 trial starts / data: Bellicum’s “Dual Switch GoCAR-T” and ON TRACK initial data
Precigen’s “Ultra-CAR-T” (trial starts: Q3)
Pivotal data / filings / approvals: Adaptimmune’s MAGE A4 SPEAR T-Cell in Synovial ON TRACK data / planned filing
Sarcoma; GSK / Adaptimmune’s NY-ESO-1 SPEAR T-Cell in Synovial Sarcoma (Ph1 data reported) (2022)
TCR-T
Other TCR platforms: TCR2’s TrUC (Mesothelin and CD19), Amgen / Immatic’s ACTengine, ON TRACK mature datasets
Ziopharm’s multi-target, personalized TCR (initial data reported)
Other T Cell First filing / approval: Iovance’s TILs lifileucel (LN-145) filing and FDA decision DELAYED
(FDA delayed planned planned filing
Therapies (melanoma) - positive pivotal data released May 2020 Q4 filing)
NK Cell data: Unmodified NK Cells (Fate’s NK100, FT500), CD16-Boosted NK Cells (Fate’s ON TRACK
NK Cell initial data +/- mature
FT516, FT538 and NantKwest’s haNK), CAR-NK cells (Fate’s FT596, Takeda’s TAK-007, (trial starts and prelim
datasets
Therapies data)
NantKwest’s CD-19.t-haNK and PD-L1.t-haNK)
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White Paper 2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond ones. There are also concerns about would prove functional. They offer both in melanoma and one or more TCR-T donor vs host immune reactions, greater scalability as well as more therapies in synovial sarcoma, which e.g., Graft vs Host Disease (GvHD). precise insertions than the traditional on the face of it are quite different Below, we will review emerging data viral transduction approaches. While indications (common vs rare, many that suggests possibly comparable these approaches are relatively new, treatments vs few, immunologically efficacy as well as an encouraging we do have several in clinic now “hot” vs “cold”). It remains to be lack of GvHD. Based on these data, with early data reported in 2020. seen what common themes, if any, it seems quite possible that the Early evidence suggests that the connect solid tumor indications where allogeneic platforms will succeed as non-viral genetic modifications are cell therapies achieve both regulatory both safe (i.e., no GvHD or any worse comparable to the viral-based ones. and commercial success. AE than the autologous ones) as While it is unlikely they would offer Overall, despite the impact of well as effective enough to achieve any efficacy benefit, their use would COVID-19 on clinical trials and registrational success. The open make manufacturing more precise R&D, in 2020 we saw numerous question is whether they will match and scalable, so if these early findings developments and hints of future the efficacy of the autologous; if they pan out we would expect rapid uptake promise that address these and are somewhat less effective but much across manufacturers. other key questions about the future quicker and cheaper, consumers will One overarching and still open of cell therapies, as well as some have to make trade-off decisions. question, which involves all forms unexpected regulatory setbacks. Another big question is whether the of cell therapy, is whether any cell We anticipate 2021 will be an enzymatic (non-viral) gene modification therapy will truly succeed in solid even richer source of new data and methods such as endonucleases tumors. Based on current data and decisions that will further characterize like CRISPR or transposon-mediated announced timelines, we could see the ultimate potential of cell therapies, approaches like Sleeping Beauty near-term approval of TILs (lifileucil) namely: 5 Blue Matter, Copyright © 2021
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2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
CD19 CAR-Ts: Competition heats up between the autologous
players - can allogeneic and next-gen designs displace?
In the almost three and a half granted a priority review for BMS / an unfortunate development for
years since the first CAR-T (Novartis’ Celgene’s autologous CD19 CAR-T stockholders as the liso-cel approval
KYMRIAH) was approved, only two liso-cel, setting the expectation that by the end of 2020 was one of three
other CAR-T therapies have been FDA it too would join them in DLBCL milestones required for a payout.
approved (Gilead’s YESCARTA just two this year. However, in May the FDA Meanwhile, both KYMRIAH and
months later, and their TECARTUS announced it was delaying its decision YESCARTA are pushing towards new
in 2020). Notably, all three of these until November 2020, citing COVID- labels in NHL. They both announced
products are autologous CD19 CAR-T 19-related delays in manufacturing positive data in FL (iNHL) at ASH, and
with a focus in NHL and B-ALL. inspections. Further delays have YESCARTA also announced positive
At the beginning of 2020, the FDA pushed the decision into 2021, data in newly-diagnosed DLBCL.
2020 YEAR-IN-REVIEW: AUTOLOGOUS CD19 CAR-T
Product Name (Manufacturer) Description Current Status & 2020 Updates
KYMRIAH • Approved in 2L+ DLBCL, 1L+ B-ALL; numerous ongoing trials
autologous, viral-transduced
(Novartis) • ASH data: Ph2 in FL (ORR=83%, CR=65%)
• Approved in 2L+ NHL; numerous ongoing trials
YESCARTA
autologous, viral-transduced • ASH data: Ph2 in indolent NHL (ORR=92%, CR=76%); Ph2 in
(Gilead)
newly-diagnosed DLBCL (ORR=85%, CR=74%)
TECARTUS autologous, viral-transduced, same as • Approved in 2L+ MCL; Ph2 in ALL ongoing
(Gilead) YESCARTA w/add’l expansion step • FDA approved (July); positive CHMP decision (Oct)
• Filed for FDA approval in 2l+ DLBCL; numerous ongoing trials
liso-cel
autologous, viral-transduced • FDA delayed decision date (was originally expected in 2020),
(BMS / Celgene)
due to COVID-19-related manufacturing inspection delays
Nex-T CD19
autologous, optimized manufacturing • Ph1 in r/r NHL
(BMS / Celgene)
At the time of this writing, direct things will heat up in 2021 if BMS’ compete in indolent NHL / FL as well.
competition between marketed liso-cel does receive FDA approval in YESCARTA has received a priority FDA
autologous CD19 CAR-T is restricted 2L+ DLBCL where it would compete review for r/r FL and KYMRIAH has
to 2L+ DLBCL, where both YESCARTA with both KYMRIAH and YESCARTA. announced a 1H21 Ph2 readout and
and KYMRIAH are approved. All Meanwhile, the KYMRIAH vs possible filing in the same indication.
other approved indications are non- YESCARTA competition will move into In the meantime, Gilead’s TECARTUS
overlapping (YESCARTA also has a earlier lines of therapy. YESCARTA (same product as YESCARTA but with
broader NHL label, KYMRIAH has a will have a Ph3 readout and possible an additional manufacturing step)
B-ALL label, and TECARTUS has an filing for 2L DLBCL as well as a Ph2 is aiming for a 2021 filing in adult-
MCL label). readout for 1L DLBCL. KYMRIAH ALL where it would compete with
To-date, Gilead’s YESCARTA enjoys will have a Ph3 readout and possible KYMRIAH.
a lead in earned revenue, however, filing for 1L DLBCL. In 2021 they will
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White Paper 2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond All four of these products are more feasible and scalable. In 2020 advancements into clinic as well as autologous (donor-derived) and we saw preliminary data that starts to early but positive readouts for several modified using viral vectors. One address both of these key questions allogeneic CD19 CAR-T, three of which open question has been whether affirmatively, which has far-reaching are also using enzymatic (non-viral) allogeneic products and non-viral gene implications beyond just the CD19 gene editing technologies: modifications methods would prove CAR-T competitive space. safe, efficacious, and importantly, Specifically, in 2020 we saw 7 Blue Matter, Copyright © 2021
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2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
2020 YEAR-IN-REVIEW: ALLOGENEIC CD19 CAR-T
Product Name (Manufacturer) Description Current Status & 2020 Updates
ALLO-501 / UCART19 • Ph1 in NHL
allogeneic, viral-transduced, safety edited
(Allogene / Cellectis / Servier) • ASCO data (n=19, ORR=63%, CR=37%)
ALLO-501A allogeneic, viral-transduced, rituximab • Ph1/2 in NHL
(Allogene / Cellectis / Servier) recognition domain deleted • Ph1/2 trial initiated (June)
• Ph1 in B Cell malignancies
CTX110 allogeneic, enzymatic-modified (CRISPR),
• Data: best dose (n=4, CR=50%); overall (n=11, CR=36%),
(CRISPR Therapeutics) safety, persistence edited
highest dose patient died of neurotoxicity
• Ph1 in NHL/B-ALL
PBCAR0191 allogeneic, enzymatic-modified (ARCUS),
• ASH data (NHL n=16, ORR=69%, CR=55%; B-ALL n=11,
(Precision Biosciences) safety edited
ORR=36%, CR=36%)
FT819 allogeneic (iSPC-derived), enzymatic-
• IND (July) for NHL/B-ALL
(Fate Therapeutics) modified (CRISPR), safety edited
For context, the registrational trials syndrome (ICANS), which is a known Fate Therapeutic’s FT819 performs, as
for KYMRIAH and YESCARTA had AE with other CAR-T cell therapies, it is the first iPSC-derived therapy to
ORR=50%/CR=32% and ORR=72%/ there has been no sign of Graft vs enter the clinic. Induced-pluripotent
CR=50%, respectively, with much Host Disease (GvHD) due to the donor stem cells (iPSC) serve as “master
higher n-values. Taken together, T cells. cell lines” which can be maintained
these initial results for the allogeneic/ While none of these manufacturers over time to offer a standardized,
enzymatic gene modified CAR-T, have announced dates for future scalable foundation for cell therapy
while not clearly superior, are certainly data releases, we expect to see manufacturing. If successful, this
promising given their other product additional interim, and possibly final, approach could streamline and
attributes. And very importantly, Ph1 readouts in 2021, as well as standardize the current patient / donor-
while there was a patient death from updates on filing timelines based on derived manufacturing approaches on
CRISPR’s CTX110 due to immune these complete datasets. It will be the market and in the clinic.
effector cell-associated neurotoxicity particularly informative to see how
BCMA CAR-Ts: which (class of) therapy will take the prize in
multiple myeloma?
In 2020 the first BCMA targeted However, the FDA unexpectedly delay has already cost them the
therapy in multiple myeloma was refused the filing, citing a need for payout). In the meantime, competition
approved, GSK’s BCMA-ADC Blenrep additional manufacturing information. continues to heat up in the BCMA
(belantamab mafodotin-blmf). BMS/ BMS refiled in July and received space - not just within CAR-T including
Celgene’s BCMA CAR-T ide-cel a March 2021 PDUFA date, which the very impressive data from J&J’s
was supposed to be hot on their would have been just in time for their cilta-cel, but also the bispecific T cell
heels, filing for FDA approval in May. milestone payout (however, liso-cel’s engagers (TCE).
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2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
In December 2020, there were data showing ORR=31%, 73% with Orva-cel is one to watch with an
numerous data releases at ASH DOR >6 months, n=97, so the CAR-T impressive 81% ORR and 39% CR.
which informed several outstanding and TCE both look quite competitive Regarding allogeneic contenders, only
questions: in terms of efficacy. Although some Allogene / Cellectis’ ALLO-715 has
• Which autologous CAR-T will take datasets are still early or small, there announced data, with a more modest
the market lead (once they are seems to be a general consensus ORR of 60%.
approved)? Cilta-cel may launch that the autologous CAR-T have the BCMA CAR-T are not only
not far behind ide-cel, with a very efficacy edge overall. In particular, competing with each other and the
impressive ORR and CR J&J / Legend’s “dark horse” approved Blenrep, however. We
• Can allogeneic compete? Unclear contender cilta-cel impressed with a saw several promising datasets
- the only allogeneic data we have nearly 100% response rate and 67% from the TCEs as well, with ORR
to-date is ALLO-715’s relatively CR. They filed for FDA approval in up to 80%. That said, these data
modest 60% ORR December, so in 2021 we may see are more preliminary with CR either
• Will bispecific / T cell engagers ide-cel and cilta-cel go head-to-head not announced, or in the case of
(TCE) offer a competitive efficacy in the market. While cilta-cel seems Regeneron’s REGN5458, none
/ safety profile? Possibly, but while to have superior efficacy, it also has achieved (63% VGPR but no CR).
the ORR is competitive, we have greater neurotoxicity, so ide-cel may In 2021 the major BCMA news will
not seen CR yet, and TCE do have be able to carve out a niche based on be the regulatory decisions for ide-cel
their own serious AEs tolerability. The BCMA CAR-T space and cilta-cel, but we also anticipate
also has emerging data for “next gen” maturing datasets in allogeneic CAR-T
For context, GSK’s BCMA-ADC autologous BCMA CAR-T, namely and TCE that will clarify how the
Blenrep was FDA approved based on BMS / Celgene’s orva-cel and bb21217. overall BCMA market will play out.
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2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
What’s Next for CAR-T Cell Therapies: other targets, technology
advances, solid tumors?
In recent years we have seen many questions about longer-term evolution • What other targets will succeed in
significant advances in the CD19 and of T cell therapies, namely: liquid tumors? Will any succeed
BCMA CAR-T spaces, but we also • How will allogeneic product in solid? See: PRG-3006, CYAD-02,
expect additional targets, indications, attributes compare to and Cellectis platform for liquid; all
and designs to reach registrational autologous? See: Celyad, Cellectis, others in solid
milestones in 2021-22. Precision Biosciences platform • Will safety / activation switches
For these earlier stage products, • How will non-viral-transduced or other modifications boost
based on their current status, in 2021 products compare to viral- outcomes? See: BPX-603 and
we expect preliminary / Ph1 data transduced? See: Precigen, Precigen platform
releases that will inform several key Precision Biosciences platform
2020 YEAR-IN-REVIEW: CAR-T CELL THERAPY EVOLUTION
Product Name (Manufacturer) Target / Description Current Status & 2020 Updates
BPX-601 PSCA CAR-T • Ph1/2 in PSCA-expressing Pancreatic, Gastric, Prostate
(Bellicum) (autologous, activation switch “GoCAR-T”) • Trial on hold after patient death
HER2 CAR-T
BPX-603 • Ph1 in HER2-expressing solid tumors
(autologous, dual safety / activation
(Bellicum) • IND (June); First patient enrolled (Dec)
switches “Dual Switch GoCAR-T”)
MUC16 CAR-T
PRGN-3005 • Ph1 in Ov, Fallopian, Peritoneal
(UltraCAR-T: autologous, Sleeping
(Precigen) • First patient dosed (Nov)
Beauty, efficacy + safety switch)
CD33 CAR-T
PRGN-3006 • Ph1 in AML
(UltraCAR-T: autologous, Sleeping
(Precigen) • First patient dosed (Nov)
Beauty, efficacy + safety switch)
• Ph1 in solid tumors (Colorectal), liquid tumors (AML/MDS)
CYAD-01 NKG2D CAR-T
• Prelim results show disease control in mCRC
(Celyad) (autologous)
• Discontinued due to “clinical futility”
CYAD-02 NKG2D CAR-T • Ph1 in AML/MDS (Chart Continues on next page)
(Celyad) (autologous, “next gen” design) • First patient dosed (Jan); 1 patient achieved CR
CYAD-101 NKG2D CAR-T • Ph1 in mCRC
(Celyad) (allogeneic) • combo study with Keytruda initiated (Sept)
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UCARTCS1A CS1/SLAMF7 CAR-T • Ph1 in MMHER2 CAR-T
BPX-603 • Ph1 in HER2-expressing solid tumors
(autologous, dual safety / activation
(Bellicum)
switches “Dual Switch GoCAR-T”)
• IND (June); First patient enrolled (Dec) White Paper
MUC16 CAR-T
PRGN-3005 • Ph1 in Ov, Fallopian, Peritoneal
(UltraCAR-T: autologous, Sleeping
2021(Precigen)
Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
• First patient dosed (Nov)
Beauty, efficacy + safety switch)
CD33 CAR-T
PRGN-3006 • Ph1 in AML
(UltraCAR-T: autologous, Sleeping
(Precigen) • First patient dosed (Nov)
Beauty, efficacy + safety switch)
• Ph1 in solid tumors (Colorectal), liquid tumors (AML/MDS)
CYAD-01 NKG2D CAR-T
(Continued from previous page) • Prelim results show disease control in mCRC
(Celyad) (autologous)
• Discontinued due to “clinical futility”
CYAD-02 NKG2D CAR-T • Ph1 in AML/MDS
(Celyad) (autologous, “next gen” design) • First patient dosed (Jan); 1 patient achieved CR
CYAD-101 NKG2D CAR-T • Ph1 in mCRC
(Celyad) (allogeneic) • combo study with Keytruda initiated (Sept)
UCARTCS1A CS1/SLAMF7 CAR-T • Ph1 in MM
(Cellectis) (allogeneic, safety edited) • FDA hold after patient death (July); trial resumed (Nov)
UCART22 CD22 CAR-T • Ph1 in B-ALL
(Cellectis) (allogeneic, safety edited) • ASH data: n=5, 2 CR, no DLT
UCART123 CD123 CAR-T • Ph1 in AML
(Cellectis) (allogeneic, safety edited) • Was on FDA hold after trial fatality, resumed dosing (Jan)
PBCAR20A CD20 CAR-T • Ph1 in NHL, CLL, SLL
(Precision Biosciences) (allogeneic, safety edited) • First patient dosed (Apr)
Non-CAR-T Cell Therapy (TCR-T, TILs, etc) - will we
see approval(s) in 2021-22?
It has been a major question TCR-T T cell therapies, which includes ORR=44% with a DCR of 94%. These
whether and when any of the purified and reinfused tumor-infiltrating are promising data for this difficult
non-CAR-T cell therapies would T cells (TILs) as well as safety-edited to treat cancer, and Adaptimmune
successfully file and launch. Here or otherwise boosted T cells that has announced they will be filing
we consider two major categories of do not have their T cell receptors with an estimated commercial launch
non-CAR-T: the first is TCR-T, where modified. Both of these categories are in 2022. GSK is likely on a similar
the endogenous T cell receptor (TCR) designed to work in solid tumors as timeline, although they have not
is swapped out for an engineered well as liquid, although efficacy has made a specific announcement. No
TCR that will detect a tumor-specific been challenging to achieve. other TCR-T is in pivotal trial nor has
antigen. The key distinction is that In 2020 there were relatively few announced timelines for filing or
CAR-T can only detect tumor-specific data updates for TCR-T, with the key launch, however we expect in 2021
antigens that are naturally expressed exception of two TCR-T approaching that additional Ph1 datasets will read
on the cell surface, whereas TCR-T registrational milestones, both in out and clarify which targets and
can detect a tumor-specific antigen synovial sarcoma. These were platforms are most efficacious. As
that is expressed anywhere within GSK / Adaptimmune’s letetresgene- in CAR-T, we expect to see data on
the cell, as long as it is appropriately autoleucel, which targets NY-ESO-1 a variety of genetic modifications
processed by the MHC cellular and delivered an ORR=20-50%, and and methods to deliver them (viral
machinery. The second category of Adaptimmune’s ADP-A2M4, which vs non-viral), as well as various pre-
non-CAR-T is the non-CAR-T, non- targets MAGE A4 and delivered an conditioning and boosting protocols.
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2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond
In 2020 we also saw some notable data for primed T cell approaches delta T cells are a subset of T cells
data and registrational progress for (Immatics / Amgen’s ACTolog and that do not require MHC presentation.
non-TCR, non-CAR T cell therapies, Repertoire’s TRQ-1501), where T cells So, they could theoretically overcome
in particular TILs. Iovance announced are extracted from the patient and this known form of tumor resistance
positive pivotal trial data for their TIL then primed against cancer neo- without triggering Graft vs Host
therapy lifileucil (LN-145) in heavily- antigens before being re-infused. Disease, which has been a concern
pretreated metastatic melanoma There is some preliminary evidence of with other allogeneic approaches.
(n=65, DCR=80%, ORR=36%). They disease control as well as persistence Therefore, they have good potential
plan to file in 2021 and could therefore of these T cells over time. And finally, as a safe and efficacious T cell-based
be the first non-CAR T cell therapy to in 2020 we saw additional gamma approach.
market. Also in 2020, we saw initial delta T cells enter the clinic. Gamma
In 2021, we expect to see major tumors and / or Tessa Therapeutic’s Amgen’s ACTolog and Repertoire’s
registrational and clinical updates. TT10 in nasopharyngeal carcinoma. RPTR-147) as well as allogeneic
Namely, we could see Iovance’s Additionally, we may see additional gamma delta T cells (TC Biopharm’s
lifileucel filing in melanoma, and Ph1 data that clarifies the potential of TCB002 and Incysus’ in GBM).
perhaps filings (or at least updates) for other T cells approaches like primed
Bellicum’s rivo-cel in pediatric liquid endogenous T cells (Immatic’s /
13 Blue Matter, Copyright © 2021White Paper 2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond Other Cell Therapies: (When) will NK Cells and new DC Vaccines succeed in clinic? NK cells, which are the cytotoxic with further progress into the clinic For DC vaccines, in 2020 there were effector cells of the innate immune which should deliver clarifying data in no major updates on clinical-stage system (as opposed to the adaptive 2021-22. programs. However, Dendreon’s immune system, which is where In 2021, we expect to see further PROVENGE delivered a new dataset T cells operate), have long been data which characterizes the efficacy showing a survival benefit over considered as a promising foundation and safety of the different NK cell standard of care androgen blockers, for cell therapy because they can iterations, including CAR-NK for CD19 and APCEDEN (not approved in the potentially recognize tumor-specific that can give us a sense of how these US) published a case study showing antigens with less risk of immune therapies will compare to CAR-T. a regression. In 2021, we will keep “overreaction”. Similar to T cells, DC “vaccines” are a cell therapy an eye out for Northwest Bio’s Ph3 there are unmodified, boosted / based on Dendritic Cells, which data release for their DCVax-L in activated, and CAR-NK iterations process tumor-specific antigens and glioblastoma, which had reported under development. In 2020 we saw activate the adaptive immune system promising earlier data on efficacy. some very preliminary data, along (T cells) to recognize and attack them. 14 Blue Matter, Copyright © 2021
White Paper Cell-Based Therapies: 2019 Year in Review and Upcoming Milestones 15 Blue Matter, Copyright © 2021
White Paper 2021 Outlook for Cell-Based Therapies in Oncology: CAR-T Expansion and Beyond Summary and Conclusions: Looking Ahead to a Competitive 2021 In addition to the specific regulatory to offer the first new treatment In conclusion, while we did see milestones and data releases advances in a long time, for example delays and set-backs in 2020 from discussed above, in 2021 we will in synovial sarcoma where two COVID-19, namely clinical trial delays also start to see cell-based therapies different TCR-T are reaching pivotal and manufacturing issues (which in position themselves within various stage, and in glioblastoma where a turn led to regulatory delays), overall competitive markets. While CD19 DC vaccine is now undergoing data the field has made much progress. CAR-T competition will largely be analysis for a completed Ph3. For both It has set the stage for an eventful in-class (between established and cancers, the current standard of care 2021-22 where we expect to see entering CD19 CAR-T), the BCMA is surgery plus chemoradiation (with multiple approvals in new targets competitive space will be active, not poor outcomes), so there is huge with the BCMA CAR-T(s) and possibly just with out-of-class BCMA therapies unmet need which cell therapies can non-CAR-T therapies as well. In like BCMA-ADC and BCMA:CD3 hopefully address. addition, we expect to see data from TCEs, but in the context of numerous In terms of longer-term out-of- the numerous Ph1 trials which are other multiple myeloma therapies class competition beyond the T continuing to enroll, which will answer like the CD38 antibodies and other Cell Engagers as discussed above, questions not just about targets and immunomodulating agents. Similarly, the success of the mRNA vaccine indications, but about the attributes of for TILs and TCR-Ts trying to break approaches in COVID hints at possible allogeneic cell sources, NK cell-based through in melanoma, they must not success in cancer as well (where therapies, and various modifications only demonstrate sufficient efficacy they are being actively developed). and modification methods (e.g., / safety for regulatory approval, they However, the early data is mixed at CRISPR-based). And finally, taken must also carve out a niche amongst best, with Moderna’s mRNA cancer together these data releases and numerous established treatments, some vaccine mRNA-4157 delivering a ORR regulatory advancements will further of which are already quite effective. of 50% (n=10) in HNSCC, and Roche clarify the ultimate potential for cell Conversely, there are indications / BioNTech’s RO7198457 delivering a therapies within the oncology market, where cell therapies have the potential very low ORR of 8% in their Ph1 trial. including out-of-class competition. 16 Blue Matter, Copyright © 2021
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This paper authored by Jeron Eaves and Pankaj Oza.
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