Poster #CT141 A Phase 1 Trial of RTX-240, an Allogeneic ...
Transcript of Poster #CT141 A Phase 1 Trial of RTX-240, an Allogeneic ...
A Phase 1 Trial of RTX-240, an Allogeneic Engineered Red Blood Cell With Cell-Surface Expression of 4-1BBL and Trans-Presented IL-15, in Patients With Advanced Solid Tumors
Omid Hamid1, Jason Luke2, Alexander Spira3, Geoffrey Kuesters4, Iga Sienczylo4, Gilad Gordon4, Melissa Johnson5 1The Angeles Clinic and Research Institute, a Cedars Sinai Affiliate, 2University of Pittsburgh, 3Virginia Cancer Specialists Research Institute, US Oncology Research, Johns Hopkins Medicine, 4Rubius Therapeutics, 5Tennessee Oncology, Sarah Cannon Research Institute
The American Association for Cancer Research Annual Meeting/April 10-15, 2021
Figure 3: RTX-240 Phase 1 Clinical Trial in Patients With Solid Tumors Trial Design
Peripheral blood immunophenotyping markers included: CD45, CD56 (NK), CD16 (NK), CD8, CD45RA, CCR7, HLA-DR, CD3, Ki67,
Granzyme B CD45, CD16 (NK), CD56 (NK), NKp30, NKG2D, NKp44, NKG2A, TRAIL, CD3, CD4, CD25, CD127, FoxP3, Ki67.
Immunofluorescence markers included: CD3, CD8, CD4, CD56, CD20, CD68, CD163, FoxP3, PD-1, PD-L1, DAPI, CK/SOX10,
Granzyme B
• Five cohorts are completed in the RTX-240 Phase 1 clinical trial in patients with solid tumors over 2 logs of dosing (1e8 to 1e10 Q4W-Q6W are completed)
• Two cohorts are open to enrollment to further explore dose and schedule (the 3e10 Q4W and a Q3W schedule at the 1e10 dose level are enrolling)
• Two routes of administration were assessed: intravenous (iv) only and 1 exploratory cohort of iv combined with 2 intratumoral (it) doses in Cycle 1
Table 1. Patient Baseline Characteristics
1Lower GI cancers include colorectal cancer (n=2), anal cancer (n=1), pancreatic ductal adenocarcinoma (n=1); melanoma includes
cutaneous melanoma (n=2), ocular melanoma (n=2), mucosal melanoma (n=1); and other cancers (all n=1), gastroesophageal,
mesothelioma, non-small cell lung, ovarian, prostate, soft tissue sarcoma, testicular germ cell tumor
Safety population N=16
Initial data cut-off: Feb 28, 2021
Table 2: Treatment Emergent Adverse Events by Grade Related to RTX-240 Observed in 2 or More Patients
Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Safety population N=16
Initial data cut-off: Feb 28, 2021
Observed Immune-Related Adverse Events (irAE)
• Ten irAE of Grade 1/2 were observed among 5 patients, no Grade 3/4 irAEs reported. Observed irAE with a median time to onset of 42 days from the first dose (range, 0-62 days)
• Grade 2 irAE include pneumonitis, adrenal insufficiency and hypothyroidism
• Grade 1 irAE include arthralgia (n=3), myalgia (n=2), AST elevation and ALT elevation
MONOTHERAPYRTX-240 Relapsed/refractory (R/R) or locally advanced solid tumors
Phase 1: Monotherapy in Solid Tumors �16 Patients Evaluable
1e8 �(n=2)
Q4W iv
1e9 �(n=3)
Q6W iv
3e9(n=3)
Q4W iv
1e10
�(n=4)Q4W iv
1e10
�(n=3)Q4W iv/it
1e10
Q3W ivOpen to
�Enrollment
3e10
Q4W iv(n=1)
Open to Enrollment
Further explore dose & schedule
PHARMACOKINETICS/PHARMACODYNAMICS: Fig 8. Peripheral Immunophenotyping
Maximum fold change is defined by the greatest result post treatment divided by baseline value. (A) Activation of NK cells is determined by fold increases in the percentage of NK cells positive for the late activation marker HLA-DR post RTX-240. (B) Expansion of the
NK cells is assessed by fold increases in the absolute number of NK cells post-RTX-240. (C) Activation of memory CD8+ T cells is determined by memory T cell expression of the late activation marker, HLA-DR. (D) Expansion of the memory CD8+ T cell population is
assessed by fold increases (from baseline) in the absolute numbers of circulating memory CD8+ T cells.
Safety, PD population: N=16 evaluable
Initial data cut-off: Feb 28, 2021
Fig 9. Peripheral Immunophenotyping of NK Population
(A) Maximum fold change in the percent of lymphocytes that are CD16+CD56dim (mature NK cells); (B) Maximum fold change in the percentage of lymphocytes that are CD56bright (immature NK cells). (C) Maximum fold change in the ratio of expression of NKG2D and
NKG2A in NK cell population. (D) Maximum fold change in the percent of NK cells expressing NKp30.
Safety, PD population (high dose only): N=8 evaluable
Initial data cut-off: Feb 28, 2021
TARGET CELL TRAFFICKING: Fig 10. Trafficking of NK and T cells to the Tumor Microenvironment
• Trafficking of both T and NK cells was observed in 2/4 patients with on-treatment tumor biopsies (1.8 to 10-fold increases). Shown in patients with metastatic mesothelioma (n=1), metastatic soft tissue sarcoma (n=1). Tumor infiltration was not observed in patients with ovarian cancer (n=1) and heavily pre-treated melanoma (n=1)
• Increased expression of PD-L1 and/or increased ratio of M1/M2 macrophages observed in 3/4 patients with solid tumors – Suggests improved immune-permissive tumor microenvironment, which may enhance innate and adaptive tumor-associated immune cell responses
• One case is shown: A 79-year-old female with mesothelioma. Treated with adjuvant pemetrexed/cisplatin at the initial diagnosis in 2016. Developed metastatic disease in 2017, treated with nivolumab and ipilimumab and palliative radiation. Enrolled in the RTX-240-01 study and was treated at the 1e9 dose level administered
EFFICACY:Table 3. Best Overall Response (BOR)
Patients are considered evaluable for BOR if receiving at least 1 dose of RTX-240 and at least 1 post-baseline imaging
assessment completed. 1 Two PRs observed, 1 confirmed and 1 is unconfirmed with both patients remaining on treatment in the study at the data
cutoff. Time to response is 16 weeks in both patients with PR; duration of response is 1 week and 16 weeks in the unconfirmed
and confirmed PR, respectively.
Initial data cut-off: Feb 28, 2021
Efficacy population, N=15 evaluable
Figure 4: Waterfall Plot of Tumor Response by RECIST v1.1
Initial data cut-off: Feb 28, 2021
• Scans were performed at baseline and every 8 weeks after the first dose. Best response by RECIST v1.1 is plotted by patient. Patients with prior PD-1/PD-L1 therapy are indicated (*)
• Patients are evaluable for best percent change with at least 1 measurable lesion (per RECIST v1.1) and a baseline and post-treatment imaging (n=14 pts evaluable, 1 patient evaluable for efficacy with non-measurable disease)
Figure 5: Time on Treatment and Response by RECIST v1.1 in All Patients
1 Patient discontinued due to clinical disease progression
Safety population: N=16 evaluable
Initial data cut-off: Feb 28, 2021
INTRODUCTION
Immune agonists and recombinant cytokines are promising treatment approaches, but have shown limited success in the clinic.
• Limitations of agonist antibodies and recombinant cytokines include: – Severe toxicity leading to a narrow therapeutic index – Diminished activity of an agonistic antibody compared with the natural ligand, – Lack of multiple signals needed to effectively activate most cell types in the anti-tumor immune response
• RTX-240 is an allogeneic cellular therapy using genetically engineered red blood cells to express 4-1BB ligand (4-1BBL) and IL-15/IL-15Rα fusion (IL-15TP) in their natural conformation on the cell surface
• RTX-240 mimics human biology by broadly stimulating adaptive and innate immunity to generate an anti-tumor response
– Improved safety due to the restricted biodistribution of red blood cells to the vasculature and spleen
• Proposed increased efficacy given synergistic and complementary effects of 4-1BBL and IL-15TP when administered together
The Phase 1/2 clinical trial of RTX-240 is designed to determine the safety and tolerability, pharmacokinetics, maximum tolerated dose, and a recommended Phase 2 dose and dosing regimen of RTX-240 in adult patients with relapsed/refractory or locally advanced solid tumors or with relapsed/refractory acute myeloid leukemia (Phase 1 only). The trial is also assessing the pharmacodynamics of RTX-240 measured by changes in T and NK cell number and function relative to baseline and anti-tumor activity.
• Initial clinical results from the solid tumor portion of the Phase 1 study are reported here
Figure 1: RTX-240 Structure
• 4-1BBL and the cytokine interleukin-15 (IL-15TP, trans-presented) activate and expand natural killer (NK) and CD8 T cells
• 4-1BBL can drive T and NK cell proliferation and activation and interferon γ (IFNγ) production
• IL-15 and 4-1BB both bridge innate and adaptive immunity by promoting T and NK cell proliferation, and NK cell cytotoxicity
Figure 2. The RED PLATFORM® is Designed to Generate Allogeneic, Off-the-Shelf Cellular Therapies
• Red Cell Therapeutics™ (RCTs™) are a new class of allogeneic, off-the-shelf cellular therapeutic candidates for the treatment of cancer and autoimmune diseases
• RCTs are enucleated red blood cells that are genetically engineered to express hundreds of thousands of copies of multiple biotherapeutic proteins on the cell surface
• Scalable and consistent manufacturing process
RTX-240 Preclinical Observations
• RTX-240 increased CD8 T cell and NK cell expansion and activation in vitro when compared to the combination of a 4-1BB agonist antibody and rIL-15
• Expansion was directly correlated with the percentage of 4-1BBL and IL-15TP expressed on the cell surface
• RTX-240 expanded key NK subsets including CD56dim NK cells, induced the expression of key NK cytotoxicity receptors in vitro, and promoted NK cell killing of the K562 myeloid leukemia cell line
• A murine surrogate for RTX-240, mRBC-240, was effective in multiple murine tumor models, promoting significant expansion of CD8 T cells and NK cells in vivo as early as Day 4 post-treatment and the expansion of differentiated NK cells in the tumors
• RTX-240 demonstrated potent immune stimulation, antitumor activity, and no observed animal toxicity, leading to the potential for a wide therapeutic window in clinical studies
4-1BBL
IL-15TP
4-1BBL
IL-15TPBROAD IMMUNE
SYSTEM STIMULATION
T CELL
RTX-240 | (4-1BBL + IL-15TP)
NATURAL KILLER (NK) CELL
Figure 6: Confirmed PR in Metastatic Squamous Cell Cancer of the Anus (ASCC)
60-year-old female with metastatic ASCC, multiple nodal metastases. Diagnosed in May 2016, treated with surgery and adjuvant mitomycin C and 5FU. Developed nodal metastases (August 2017). First-line therapy with LY3300054 (anti-PD-L1). Second- line therapy with atezolizumab and KY1044 (anti-ICOS). PD-L1 status unknown. Disease burden includes 2 nodal target lesions (images) and 2 non-target nodal lesions (not included in images).
Treated with RTX-240 in the third-line setting. No adverse events reported. Time to response 16 weeks, duration of response 16 weeks. 54% reduction in target lesions. Patient remains on study at time of data cut-off.
Figure 7: Unconfirmed PR in Metastatic Uveal Melanoma
54-year-old male with metastatic uveal melanoma, multiple hepatic metastases. Diagnosed in August 2018, treated with enucleation and radiation. Developed liver metastases approximately 1 year later (July 2019). First-line therapy with nivolumab/ipilimumab (8 months prior to enrollment in RTX-240-01) with slow progression over the 8 months. Ipilimumab discontinued due to Grade 3 hepatitis. Treated with RTX-240 in the second-line setting. Overall burden of disease with 1 target lesion of 10 mm and >14 other evaluable lesions. Developed adrenal insufficiency and hypothyroidism early in Cycle 3 (Day 60 following the first dose of RTX-240, managed with steroids).
Complete regression of 14/15 hepatic metastases at 16 weeks with a single non-target hepatic lesion remaining. Time to response 16 weeks, duration of response, 1 week. Patient remains on study at time of data cut-off.
RED PLATFORM®
ONE �HEALTHY�O- DONOR
EXPANSION & �DIFFERENTIATION
PROGENITOR �CELL COLLECTION
LENTIVIRAL VECTORENCODING OF A
CO-STIMULATORYMOLECULE & CYTOKINE
ENUCLEATION & MATURATION
100-1000’s �OF DOSES
RED CELL THERAPEUTIC
METHODS
PARAMETERN=16 EVALUABLE
Age (median, range) 55 (23-80)
8/8
11
5
4
5
7
11
3 (1-10)
5
12
7
Gender (Male/Female)
Race/Ethnicity
Disease setting1
Colorectal/lower GI cancers, n
Prior anti–PD-1/PD-L1
Prior ipilimumab + nivolumab
Prior chemotherapy
Prior radiation
Non-Hispanic/Non-Latino
Hispanic/Latino
Melanoma, n
Other cancers, n
Lines of prior therapy in the metastatic setting, median (range)
RESULTS
ADVERSE EVENT PREFERRED TERMGRADE 1
n (%)GRADE 2
n (%)GRADE 3
n (%)GRADE 4
n (%)ANY GRADE
n (%)
Fatigue
Chills
Decreased Appetite
Arthralgia
Nausea
Pyrexia
Myalgia
Dysgeusia
Hyperhidrosis
2 (13)
3 (19)
3 (19)
3 (19)
3 (19)
2 (13)
2 (13)
2 (13)
2 (13)
2 (13)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4 (25)
3 (19)
3 (19)
3 (19)
3 (19)
2 (13)
2 (13)
2 (13)
2 (13)
RESPONSE EVALUATIONN=15 EVALUABLE
Complete response
Partial response
Stable disease
Progressive Disease
Disease control (SD, >12 weeks or PR)
0
21
6
7
6
100
50
0
-50
-100
* * * * * * * * * *
cPR(ongoing)
uPR(ongoing)
*
Be
st P
erc
en
t C
han
ge
in T
um
or
Siz
e fr
om
Bas
elin
e
0 50 100 150 200 250
Time of Treatment (days)
Partial response
Metastatic Anal Cancer
Metastatic Uveal Melanoma
Stable disease
Progressive disease
Treatment ongoing with RTX-240
Treatment arm: 1e8 Q4W 1e9 Q6W 3e9 Q4W 1e10 iv Q4W 1e10 iv/it Q4W 3e10 iv Q4W
BaselineJune 2020
C7D1Dec 2020
-51% targets (PR)
C9D1Feb 2021
-54% targets (PR)
C3D1Aug 2020
-17% targets (SD)
C5D1Oct 2020
-34% targets (PR)
BaselineOct 2020
Target Lesion (10mm)
Cycle 3 Day 1Dec 2020
Target Lesion (SD, 10 mm)
Cycle 5 Day 1Feb 2021
Target Lesion (-100%, PR)
BaselineOct 2020
Non-Target Lesion
Cycle 3 Day 1Dec 2020
Non- Target Lesion
Cycle 5 Day 1Feb 2021
Non-Target Lesion
BaselineOct 2020
Non-Target Lesion
Cycle 3 Day 1Dec 2020
Non- Target Lesion
Cycle 5 Day 1Feb 2021
Non-Target Lesion
Hepatic target lesion
A. Maximum Fold Change in the Percent of NK Cells Expressing HLA-DR
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e 4
3
2
1
Low Dose High Dose
0
Baseline
Baselin
e
Post-tr
eatment
Baselin
e
Post-tr
eatment
B Maximum Fold Change in the Absolute Number of Circulating NK Cells
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e 3
2
1
0
Baseline
Baselin
e
Post-tr
eatment
Baselin
e
Post-tr
eatment
Low Dose High Dose
C Maximum Fold Change in the Percent of Memory CD8+ T Cells
Expressing HLA-DR
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e 6
4
2
0
Baseline
Baselin
e
Post-tr
eatment
Baselin
e
Post-tr
eatment
Low Dose High Dose
D Maximum Fold Change in the Absolute Number of Circulating
Memory CD8+ T Cells
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e 4
3
2
1
0
Baseline
Baselin
e
Post-tr
eatment
Baselin
e
Post-tr
eatment
Low Dose High Dose
Low dose = 1e8-3e9 cells/dose (n=8);
High dose = 1e10-3e10 cells/dose (n=8)
A BMaximum Fold Change in the Percent of Lymphocytes
that are CD16+CD56dim
Maximum Fold Change in the Percent of Lymphocytes that
are CD56bright
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e
4
5
3
2
1
High Dose
0
20
1510
5
0
Baseline
Baseline
Baselin
e
Post-tr
eatment
Baselin
e
Post-tr
eatment
High Dose
C DMaximum Fold Change in the Ratio of Expression of
NKG2D/NKG2A of All NK Cells
Maximum Fold Change in the Percent of NKp30+NK Cells
High Dose
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e 5
4
3
2
0
1 Baseline
Baselin
e
Post-tr
eatment
High Dose
Max
imu
m F
old
Ch
ang
e f
rom
Bas
elin
e 3
2
1
0
Baseline
Baselin
e
Post-tr
eatment
High dose = 1e10-3e10 cells/dose (n=8)
Archival diagnostic biopsy On-treatment biopsy Day 34 (2 iv doses) On-treatment biopsy Day 34 (2 iv doses)
GmzB CD3 (T cells) CD8 (T cell) CD56 (NK cell)
• 10-fold increase in % of NK cells
• More than 4-fold increase in CD8+ T cells
• Improved immune-permissive environment via increase in PD-L1 expression
On-treatment, % (fold change)Baseline, %
% NK (CD56) of all cells
% All T (CD3) of all cells
% Cytotoxic T (CD8) of all cells
PD-L1+ cells
0.4
4
2
29
4.5 (10-fold)
16 (4-fold)
8.8 (>4-fold)
51 (1.8-fold)
CONCLUSIONS
• RTX-240 has a favorable safety profile at the dose levels tested with no related Grade 3/4 adverse events, minimal irAEs and no dose limiting toxicities observed to date
• RTX-240 activated and expanded both T and NK cells, which led to 2 partial responses in anal cancer and metastatic uveal melanoma
• RTX-240 induced tumor trafficking of both NK and T cells into the tumor microenvironment in solid tumors
• RTX-240 induced activation and expansion along with tumor trafficking of the two key target cell subsets in the innate and adaptive immune system: the NK cells and memory CD8+T cells
• Enrollment continues in the Phase 1 portion of the study. RTX-240 is expected to enter a Phase 1 combination trial with an anti-PD-1 therapy in 2H'21 and a Phase 2 trial in specific tumor types in 2022
Poster #CT141