Off-the-shelf CAR NK
cells potently control multiple tumor types
(117) FT536 Path to IND: Ubiquitous
targeting of solid tumors with an off-the-shelf, first-of-kind MICA/B-specific
CAR-ink cellular immunotherapy
Bryan Hancock, PhD (Fate Therapeutics) previewed the
preclinical studies supporting the investigational new drug application for FT536,
a CAR NK cell product derived from an inducible pluripotent stem-cell line
engineered for enhanced effector cell functionality, persistence, and
multi-antigen targeting capabilities through CD16-mediated antibody dependent
cellular cytotoxicity (ADCC). FT536 carries a CAR targeting the pan-tumor
associated antigens MICA and MICB (MICA/B) and the product can be consistently
and uniformly produced as well as cryopreserved at clinical scale. Potent and
persistent antigen-specific cytotoxicty was demonstrated against an array of
solid and hematological tumor lines. Activity of FT536 was further augmented
when combined with chemotherapies and/or radiation that induced surface MICA/B
expression. Multi-targeting through the CAR and CD16-mediated ADCC was also
demonstrated when FT536 was combined with trastuzumab or cetuximab for HER2- or EGFR-expressing tumors, respectively. In xenograft models, directly thawed frozen FT536 significantly
slowed tumor growth, which was further enhanced when infused in combination
with the monoclonal antibodies. Sustained persistence of FT536 for 33 days
post-infusion were also seen in a murine model of lung adenocarcinoma. These
preclinical findings support further development of FT536 as a universal
adoptive cell therapy.
Anti-CD47 shrinks breast cancer brain metastases
(270) Anti-CD47 immunotherapy as a
therapeutic strategy for the treatment of breast cancer brain metastasis
Jessica D. Mackert, PhD (Wake Forest University) described
preclinical data supporting CD47 as a target for the treatment of brain
metastases in triple-negative breast cancer (TNBC). The “don’t eat me signal” CD47
is a pleitropic surface marker expressed on numerous cell types that inhibits
myeloid cell phagocytic activity through binding SIRPalpha as well as an antagonizes
T cell function mediated by interaction with matricellular protein
Thrombospondin-1. Patient biopsies revealed an 89% increase in CD47 expression by
immunohistochemistry in metastatic brain TNBC tumors compared to primary
lesions. In mice bearing brain metastatic 4T1br3 tumors, anti-CD47 treatment
shrank tumors by roughly 50% compared to controls, which accompanied by a
5-fold increase in expression of F4/80 macrophage markers in the tumors. A
total of 318 differentially expressed genes were associated with anti-CD47
treatment, with enrichment for reduced signatures of extracellular matrix
remodeling and upregluation of pathways involved in tertiary lymphoid structure
formation. Knockout of CD47 led to 60% increased survival and 89% decreased
metastatic brain lesions in 4T1-bearing mice compared to controls. This
preclinical data supports CD47 as a potential target for the immunotherapeutic
treatment of brain metastases.
DNA vaccine plus pembrolizumab for
metastatic prostate cancer
(350) Phase II trial of a DNA
vaccine with pembrolizumab in patients with metastatic, castration-resistant
prostate cancer (mCRPC)
Douglas G. McNeel, MD, PhD (Carbone
Cancer Center, University of Wisconsin) presented the final analyses from
Arms 3 and 4 of a phase I/II study evaluating the pTVG-HP prostatic acid
phosphatase (PAP) DNA vaccine in combination with pembrolizumab for metastatic
castrate-resistant prostate cancer (mCRPC). In arm 3, the PAP DNA vaccine was
given every 3 weeks (with pembrolizumab every 3 weeks) and in Arm 2, the vaccine
was given every 2 weeks (with pembrolizumab every 4 weeks). The median time to
progression (TTP) at the time of abstract preparation was 5.3 months for Arm 3
and 8.0 months for Arm 4. Updated 6-month disease control rates presented at
the meeting were 10% and 45% of patients in Arms 3 and 4, respectively. Treatment-related adverse events ≥ grade 2
occurred at a rate of 42% across arms, and development of an immune-related
adverse event was associated with prolonged TTP. Persistent increases in serum
levels of interferon gamma and granzyme B were observed in both Arms (6/20
patients in Arm 4 and 2/20 patients in Arm B). These data suggest that the
generation of tumor-antigen-specific T cells through vaccination may help
overcome primary resistance to anti-PD-1 monotherapy in prostate cancer.
Ibrutinib enhances CLL CAR-T cell
therapy
(449) Concurrent ibrutinib enhances
T cell function in patients with chronic lymphocytic leukemia (CLL) treated
with lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T
cell therapy
Jerill Thorpe, MS (Bristol Myers
Squibb) described translational data supporting potential synergy between Bruton
tyrosine kinase inhibitors (BTKi) and CAR T cell therapy in patients with
chronic lymphocytic leukemia (CLL). Using a novel low-input RNA-seq method,
CAR-positive and endogenous T cells were isolated from the patients treated in
the TRANSCEND CLL 004 study, which evaluated the CD19-directed CAR T cell
product lisocabtagene maraleucel (liso-cel) given with the BTKi ibrutinib (n =
19) or as monotherapy (n = 16). At 1 and 2 months post-liso-cel infusion, both
populations of cells in the combination ibrutinib plus liso-cel group
demonstrated positive enrichment for expression of cell proliferation genes and
negative enrichment for expression of inflammation-associated genes compared to
what was seen with monotherapy, though the extent was lesser in the endogenous
lymphocytes. Increased CAR+ T cell expansion, reduced serum IL-6, and increased
and sustained CLL ibrutinib gene expression score—which has previously been
correlated with higher rates of undetectable minimal residual disease and longer
progression-free survival—was also seen in the combination group. The
expression of T cell exhaustion genes was reduced in CAR-positive cells from
the combination group, which was associated with improved progression-free
survival. These findings suggest that the addition of ibrutinib to CAR T cell
therapy for CLL.
TIL therapy plus pembrolizumab leads
to durable responses
(492) Phase 2 efficacy and safety
of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination
with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced
cancers
David O’Malley, MD (Ohio
State University) reported early efficacy and safety results
from two ongoing multicenter phase II clinical trials investigating autologous
tumor-infiltrating lymphocyte (TIL) therapy combined with pembrolizumab for the
treatment of head and neck squamous cell carcinoma (HNSCC), melanoma, and
cervical cancer. Patients’ tumors were first resected for TIL isolation and
manufacturing, followed by one dose of pembrolizumab, lymphodepletion, TIL
infusion intravenous IL-2, and then continued pembrolizumab for ≤ 24 months.
All enrolled patients had high tumor burdens. At median follow-up of 9.7
months, the objective response rates in the full analysis set presented
at the meeting were 60%, 39%, and 57%, for patients with melanoma, HNSCC, and cervical cancer, respectively. Almost all efficacy-evaluable patients
achieved a reduction in tumor burden. Ongoing durable responses at data cutoff
were observed in 10 of 17 patients with objective tumor response. Reporting
tolerable safety results thus far, the authors advocate for further
investigation of this combination immunotherapy strategy as an early line of
therapy option for patients with advanced solid tumors.
Intact lymph nodes are essential for
checkpoint inhibitor efficacy
(601) Sequencing Immunotherapy before
Lymphatic Ablation Unleashes cdc1-Dependent Antitumor Immunity in HNSCC
Robert Saddawi-Konefka, MD,
PhD (UC San Diego) presented preclinical evidence to determine
the best sequence of therapies for head and neck squamous cell carcinoma
(HNSCC) based on spatially distinct patterns of immune responses in cervical
lymphatic basins. In murine models of neck dissection (ND) to remove orthotopic
tobacco-signature HNSCC tumors, enrichment for conventional type I dendritic
cells (cDC1)and type I interferon signaling was observed within the resected
lymphatics. After ND, the tumor microenvironment was observed to be largely
immunosuppressed, suggesting a loss of effector function after curative-intent
surgery. Specifically, ND resulted in loss of tumor-specific CD8+ T cells and
increases in myeloid suppressive cells. Supporting this, poor immune responses
were observed with immune checkpoint inhibitors (ICIs) following cervical
lymphatic ablation. ICIs given neoadjuvantly, however, resulted in a systemic distribution
of memory anti-tumor T cells, lymph node accumulation of cDC1, and complete
responses in tumors. Interestingly, administration of ICIs prior to surgery was
also associated with reduced occurrence of occult nodal metastases at late time
points (1 week after the last ICI dose), but not when surgery was performed at
an early time point (1 day after the last ICI dose) providing preclinical
evidence for the importance of the draining lymph node in generation and
maintenance of prolonged anti-tumor responses.
Safety data support COVID-19 vaccination for checkpoint
inhibitor-treated patients
(625) COVID-19 vaccination in
patients with renal cancer or melanoma receiving immune checkpoint inhibitors
Hannah E. Dzimitrowicz, MD (Duke University) described no
increased incidence of immune-related adverse events nor severe side effects
associated with COVID-19 vaccination for patients receiving checkpoint
inhibitors—a population that was excluded from the registration trials leading
to Food and Drug Administration (FDA) approval. Retrospective data on balanced
cohorts of patients with renal cell carcinoma and melanoma undergoing
checkpoint blockade therapy who received one dose of an FDA-approved vaccine was
presented. Half of the patients were being treated with anti-PD-1 monotherapy
at the time of vaccination. Among the 40% of patients being treated with
immunotherapy combinations, 10% of patients were receiving anti-PD-1 plus
anti-CTLA-4 and 28% had a regimen that included anti-PD-1 plus a tyrosine
kinase inhibitor. Higher rates of symptoms secondary to vaccination were reported
by the ICI-treated patients, including fever, chills, arm pain, myalgias,
lymphadenopathy, headache, and diarrhea, likely related to more frequent
follow-up compared to the control group. The rates of new or worsening immune-related
adverse events after vaccination was no higher than predicted by expected historical
ICI-associated toxicity incidence rates. Only 12% of patients required a hold
of checkpoint inhibitor therapy, steroids, or hospitalization due to
immune-related toxicity. Some patients did develop COVID-19 after partial
vaccination. Further studies with larger cohorts of patients are needed to
assess efficacy of the approved COVID-19 vaccines in ICI-treated patients, yet
these data indicate vaccination is safe for this vulnerable population.
STING agonism alters stroma to turn cold tumors hot
(758) High-potency synthetic STING
agonists rewire the myeloid stroma in the tumour microenvironment to amplify
immune checkpoint blockade efficacy in refractory pancreatic ductal
adenocarcinoma
Akash R. Boda, MS (University of Texas
MD Anderson UTHealth Graduate School of Biomedical Sciences) provided the first
detailed mechanistic characterization of how synthetic agonists of the
Stimulator of Interferon Genes (STING) adaptor protein perturb the myeloid
stroma toward proinflammatory phenotypes. Multi-omics profiling on M2
macrophages and myeloid-derived suppressor cells of both human and murine
origin revealed that exposure to synthetic cyclic dinucleotides (high-potency
agonists of STING) rewired these cell populations via inhibition of c-Myc
signaling, alteration of energy metabolism away from fatty acid oxidation in
favor of oxidative phosphorylation, and antagonism of proliferation. In
orthotopic mouse models of KRAS-driven pancreatic ductal adenocarcinoma
(PDAC)—an immunologically cold tumor—intratumoral injection of synthetic
cyclic dinucleotides concomitant with checkpoint blockade led to enhanced T and
NK cell infiltration along with improved disease control. Multiparametric flow
cytometry analysis of tumors from mice treated with the combination of STING
agonists and checkpoint inhibitors confirmed that remodeling of the myeloid
stroma toward proinflammatory phenotypes with accompanying enhancements in T
cell function were both associated with therapeutic benefit. The study not only
offers new insight into the mechanisms by which cyclic dinucleotides act as
immune adjuvants for anti-tumor responses, but also highlight the potential of
these compounds to reverse primary resistance to checkpoint blockade in
immunologically cold tumors such as PDAC.
Skin toxicity predicts
improved survival with checkpoint blockade
(814) Cutaneous Immune-related Adverse Events are
Protective of Mortality in Patients Treated with anti-PD1 and anti-PDL1 therapy
in a multi-institutional cohort study
Yevgeniy Semenov, MD (Massachusetts General
Hospital/Harvard Medical School) presented a retrospective study that included 7,008 patients who
developed cutaneous immune-related adverse events (cirAEs) within 6 months of
treatment initiation of anti-PD-(L)1 therapy as well as 7,008 control-matched
patients that did not experience skin toxicity. Landmark analyses at 6 months
showed statistically significant improvement in overall survival among the
patients who developed any cirAE as well as individual
toxicities including nonspecific rashes, pruritus, drug eruption, and xerosis.
Other cirAE morphologies also demonstrated a trend toward improved survival
without reaching statistical significance. The onset of a cirAE within 3 months
or 9 months of first dose of PD-(L)1 inhibitor was similarly associated with a
reduced risk of death (HR 0.759, p < 0.0001 for a 3 month landmark time; HR
0.84, p < 0.0001 for a 9 months landmark time). These data suggest that many
dermatologic irAEs may be predictive of survival benefit from anti-PD(L)1
therapy.
Combination pembrolizumab plus oncolytic virus improves CR
rates for NMIBC
(955) CORE1: Phase 2, Single Arm
Study of CG0070 Combined with Pembrolizumab in Patients with Non Muscle
Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG)
Roger Li, MD (Moffitt Cancer
Center) reported early data from a phase II study of an intravesical
oncolytic virus combined with systemic pembrolizumab therapy for the treatment
of BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). CG0070 is a
GM-CSF-expressing adenovirus engineered to harbor the transcription factor E2F,
which allows for preferential replication in tumor cells with defects in the
tumor suppressor protein retinoblastoma—resulting in lysis and immunogenic cell
death. Encouraging CR rates have been reported previously in separate studies
of CG0070 and pembrolizumab monotherapies for NMIBC, and this is the first
trial assessing a combination approach. The primary study endpoint is CR at 12
months, with secondary endpoints of CR at any time, progression-free survival,
duration of response, cystectomy-free survival, and safety. At the time of
abstract submission, 5 out of 5 assessed patients had achieved CR at 3 months,
and there were no grade ≥ 3 adverse events reported. Updated data presented at
the meeting confirmed the 100% CR rate at 3 months in 2 additional patients and
demonstrated ongoing CRs at 6 and 9 months for the 2 and 6 patients for whom
longer follow-up was available. These preliminary data support further evaluation
of CG0070 plus pembrolizumab, a combination that has demonstrated unprecedented
CR rates, has been well-tolerated to date and may exhibit synergistic
anti-tumor effects.