Poster · 2022 · SITC

COMMANDER-001: A Phase 1/2, First-in-Human, Multicenter, Open-Label Study of SQZ-eAPC-HPV as Monotherapy and in Combination with Pembrolizumab in Patients with HPV16+ Recurrent, Advanced, or Metastatic Solid Tumors—Trial in Progress

Meredith S. Pelster, Michael Gordon, Tricia Wise-Draper, Jong Chul Park, Wade T. Iams, Julia J. Jennings, Nathan Miselis, Rui-Ru Ji, Scott Loughhead, Ricardo Zwirtes, Howard Bernstein, Armon Sharei, Antonio Jimeno, Sarah Cannon

Publication text

E Addressable Patient Population (%)

Sqz-pbmc-

Hpv

SQZ-eAPC-

Hpv 0 4 8 12 16 20 24

Hours Max Presentation (%) SQZ-PBMC-HPV SQZ-eAPC-HPV B IFNγ+CD45RO+ (% of CD3+CD8+)

Sqz-pbmc-

Cmv

SQZ-eAPC-

Cmv

D Figure 3: SQZ-eAPC-HPV is an improved SQZ® clinical therapeutic candidate. A. SQZ® eAPC is an HLA agnostic drug product with a broader antigen repertoire, potentially increasing the addressable patient population by 2-3x. B. Preclinically, duration of presentation of HPV16 antigens is longer lasting with SQZ® eAPC compared to the SQZ® PBMC clinical therapeutic candidate. C. In humanized mice treated with SQZ® PBMC or SQZ® eAPC, SQZ® eAPC elicits a greater CD8+ T cell response. D. The addition of mRNAs encoding for signals 2 or 3 in SQZ® eAPC enhances T cells responses compared to the CpG maturation used to stimulate signal 2 in SQZ® PBMC. E. A table summarizing the key similarities and differences between the SQZ® PBMC-derived therapeutic candidates. SQZ® eAPC Enhancements C COMMANDER-001: A Phase 1/2, First-in-Human, Multicenter, Open-Label Study of SQZ-eAPC-HPV as Monotherapy and in Combination with Pembrolizumab in Patients with HPV16+ Recurrent, Locally Advanced, or Metastatic Solid Tumors (Trial in Progress) Meredith S. Pelster, Michael Gordon, Tricia Wise-Draper, Jong Chul Park, Wade T. Iams, Julia J. Jennings, Nathan Miselis, Rui-Ru Ji, Scott Loughhead, Ricardo Zwirtes, Howard Bernstein, Armon Sharei, Antonio Jimeno, Sarah Cannon Research Institute at Tennessee Oncology (Nashville, TN), HonorHealth Thompson Peak Medical Center (Scottsdale, AZ), University of Cincinnati Medical Center (Cincinnati, OH), Massachusetts General Hospital (Boston, MA), Vanderbilt University Medical Center (Nashville, TN), SQZ Biotechnologies (Watertown, MA), University of Colorado Cancer Center (Aurora, CO)

Background

Antigen-specific CD8+ T cells are critical for mounting a potent immune response against tumors. Creation of T cell responses requires 3 key signals

from antigen presenting cells (APCs) (Figure 1B):

Signal 1. the peptide-MHC complex binding to the T cell receptor
Signal 2. costimulatory molecules that bind to T cell stimulatory domains, and
Signal 3. inflammatory cytokines binding to receptors on T cells.
To create enhanced APCs (eAPCs) from peripheral blood mononuclear cells (PBMCs), Cell Squeeze® technology is used to deliver mRNAs encoding

HPV16 E6 and E7 antigens (signal 1), CD86 (signal 2), and membrane-bound IL-2 and IL-12 cytokines (signal 3) (Figure 1).

Co-localizing signal 2 and 3 molecules on the eAPC surface potentiates T cell responses in in vitro human and in vivo humanized mouse models when

compared to antigen alone. Clinically, this may enable more potent T cell stimulation and limit off-target effects from systemic exposure to signal 2 and 3 (Figure 2).

SQZ-eAPC-HPV is an enhanced SQZ® clinical therapeutic candidate, with no HLA restrictions, that leverages the clinical and manufacturing

experience of the SQZ-PBMC-HPV product (Figure 3). This approach may potentially enable rapid implementation across other tumor types as it facilitates exchange of mRNA to encode for other antigens or T cell activation signals.

Summary

SQZ-PBMC-HPV SQZ-eAPC-HPV Differentiation Cell Type PBMC PBMC N/A Delivery material E6/E7 synthetic long peptide E6, E7, CD86, mbIL-2, and mbIL-12 mRNA More epitopes, longer duration of presentation, signal 2&3 Maturation 4 hr CpG incubation None Improved yield and shorter process time Anticipated T cell response HLA-A*02 restricted CD8+ T cell response HLA agnostic CD8+ T cell response. Potential for CD4 T cell response Broader, better stimulated T cell response across HLA types Sites of Priming Spleen and lymph Nndes Spleen and lymph nodes N/A Figure 1: Cell Squeeze® technology and antigen presentation approach. A. Peripheral blood mononuclear cells (PBMCs) are collected from the patient and squeezed with mRNA encoding for full length E6 and E7 proteins, CD86, membrane bound IL-2 and membrane bound IL-12, resulting in SQZ-eAPC-HPV. SQZ-eAPC-HPV is intravenously administered to the patient. SQZ-eAPC-HPV cells then migrate to the lymphoid organs where they are designed to activate CD8 T cells. B. mRNA transcripts encoding for full length E6 and E7 proteins, CD86, membrane bound IL-2 and membrane bound IL-12 are introduced into the cytosol of PBMCs using Cell Squeeze® technology. After IV administration of SQZ-eAPC-HPV, the mRNAs are expected to be translated resulting in signal 1, 2, and 3 activation and ultimately activation of HPV16 specific CD8 cells. Cell Squeeze® Technology and SQZ-eAPC-HPV A SQZ-eAPC-HPV Overview B PBMCs + mRNAs Cell Squeeze ® SQZ® eAPCs Lymph Node Spleen Tumor Figure 6: Collection to release for a patient. Eligible patients will undergo a single leukapheresis. In our GMP compliant manufacturing process, patient cells are processed in less than 24 hours to generate cryopreserved drug product. The time from leukapheresis to product release for the 1st administration is approximately one week. Patients do not require a conditioning regimen before the 1st administration; SQZ-eAPC-HPV is administered outpatient after the first dose. Leukapheresis SQZ Process <24-hours QC and Batch Release Administration to Patient SQZ-eAPC-HPV Manufacturing and Patient Experience

COMMANDER-001 (NCT05357898) leverages

clinical and manufacturing experience from SQZ- PBMC-HPV-101 (NCT04084951), in which an unconfirmed partial response was observed in a patient receiving SQZ-PBMC-HPV monotherapy at the recommended phase 2 dose.

COMMANDER-001 is open for enrollment to

patients with HPV16+ recurrent, locally advanced or metastatic solid tumors and includes a Monotherapy Dose Escalation Phase and a Combination Safety Phase with pembrolizumab (Figure 4). The study is being conducted at sites in the United States (Figure 5).

Eligible diseases are all HPV16 driven cancers

(including anal, cervical, head and neck, penile, vaginal, and vulvar).

Patients will receive SQZ-eAPC-HPV q3w for up to

1 year or until available autologous drug product is exhausted.

Eligible patients will undergo a single

leukapheresis collection at the study site. (Figure 6).

Treatment does not require a preconditioning

regimen, e.g. immuno- or myeloablative regimen.

Dose limiting toxicity (DLT) period is 28 days for the

monotherapy phase and 42 days for the combination phase.

Patients must have a lesion that can be biopsied at

Screening and on study. Study Design Participating Study Centers Figure 5: Map of participating sites COMMANDER-001 is a phase 1/2 study being conducted in the United States. Three sites are currently open to enrollment (blue); more site are expected to open soon (orange). Open and Enrolling: Sarah Cannon Research Institute at Tennessee Oncology, Honor Health, University of Colorado; Sites Coming Soon: Massachusetts General Hospital, University of Cincinnati Medical Center, Vanderbilt University Medical Center Study Assessments

Safety and tolerability to identify the monotherapy

recommended phase 2 dose (RP2D) and RP2D in combination with pembrolizumab

Preliminary evidence of antitumor activity of SQZ-eAPC-HPV

monotherapy and in combination with pembrolizumab will be evaluated per RECIST 1.1 every 6 weeks for the first 2 scans, then every 8 weeks thereafter

Manufacturing feasibility of SQZ-eAPC-HPV
Exploratory endpoints include the following:
Assess the pharmacokinetics of SQZ-eAPC-HPV
Characterization of CD8 cells in tumor and blood.
Potential mechanism of resistance
Cytokine responses
Other pharmacodynamic evaluations such as circulating cellfree HPV16 DNA levels in plasma

Methods

Figure 4: COMMANDER-001 Study Design DLT period = 42 days Recurrent or metastatic HPV-16+ cancer HLA agnostic ICI-naïve patients (≤1 prior lines) Part 2: Lead-in Phase (Requires DSMB approval) SQZ-eAPC-HPV RP2D + pembrolizumab 200 mg q3w SQZ-eAPC-HPV RP2D 6w Recurrent or metastatic HPV-16+ cancer HLA agnostic Platinum experienced CPI experience/offered Part 1: Monotherapy Phase (1A) and Combination Phase (1B) Safety and Tolerability Manufacturing Feasibility Efficacy (ORR) Biomarkers SQZ-eAPC-HPV 2.5 x106/kg q3w SQZ-eAPC-HPV 5.0 x106/kg q3w SQZ-eAPC-HPV RP2D q3w + pembrolizumab 200 mg q3w n = 6 to 12 BOIN SQZ-eAPC-HPV 0.5 x106/kg q3w SQZ-eAPC-HPV RP2D-1 q3w + pembrolizumab 200 mg q3w n = 6 to 12 BOIN Dose de-escalation if DLT >30% Safety and Tolerability Manufacturing Feasibility Efficacy (ORR) Biomarkers Inclusion Criteria Inclusion Criteria Objectives Objectives DLT period = 28 days DLT period = 42 days Part 1A: SQZ-eAPC-HPV monotherapy will be tested with at least 3 different dose levels to identify the recommended phase 2 dose (RP2D). Additional higher or lower dose cohorts may be opened. Part 1B: SQZ-eAPC-HPV RP2D is tested in combination with 200 mg pembrolizumab. Pembrolizumab will be given on Cycle 1 Day 8. In subsequent cycles, after SQZ-eAPC-HPV on Day 1 of each cycle. Part 2: Lead-in SQZ-eAPC-HPV RP2D is tested in combination with 200 mg pembrolizumab. SQZ-eAPC-HPV is given as a monotherapy for the first 2 cycles, then from Cycle 3 pembrolizumab will be given on Day 1 after SQZ-eAPC-HPV.

A B

Figure 2: SQZ® eAPCs are capable of expanding autologous CD8+ T cells. Cell Squeeze® processed PBMCs were co-cultured with donor matched unprocessed PBMCs that served as a source of reactive CD8+ T cells. Following a 5-day co-culture, cells were stimulated with antigen mRNA and evaluated via intracellular cytokine staining for IFNγ (A) and TNFα (B). Squeezing all 4 mRNAs into PBMCs resulted in a significant increase in IFNγ and TNFα levels compared to antigen mRNA alone or CD86+mbIL-2+mbIL-12 mRNAs alone. SQZ® eAPC Preclinical Data A Presented at SITC 2022, Nov 8-12, 2022

Acknowledgements

We thank the patients, their families, and their caregivers for their time and their willingness to participate in this study. We also thank the investigators and the investigational site staff for their contributions to the study.

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Some publications reference SQZ Biotechnologies, a company Dr. Armon Sharei and colleagues previously founded. Portal is the next generation company leveraging Dr. Sharei's platform technology.

# COMMANDER-001: A Phase 1/2, First-in-Human, Multicenter, Open-Label Study of SQZ-eAPC-HPV as Monotherapy and in Combination with Pembrolizumab in Patients with HPV16+ Recurrent, Advanced, or Metastatic Solid Tumors—Trial in Progress This page is a text version of a Portal Biotechnologies publication. The bibliographic record is labeled in the text so it can be read without the surrounding website. ## Bibliographic record - Title: COMMANDER-001: A Phase 1/2, First-in-Human, Multicenter, Open-Label Study of SQZ-eAPC-HPV as Monotherapy and in Combination with Pembrolizumab in Patients with HPV16+ Recurrent, Advanced, or Metastatic Solid Tumors—Trial in Progress - Document type: Poster - Year: 2022 - Outlet: SITC - Page URL: https://portal.bio/publications/2022-commander-001-a-phase-1-2-first-in-human-multicenter-open-label-study-of-sqz-eapc-hpv--ajkGhBEAACgAc96l - Markdown URL: https://portal.bio/publications/2022-commander-001-a-phase-1-2-first-in-human-multicenter-open-label-study-of-sqz-eapc-hpv--ajkGhBEAACgAc96l.md - Original file: https://portal-bio.cdn.prismic.io/portal-bio/65ccd66f9be9a5b998b5d0a1_SQZ_COMMANDER-001_TiP_Poster_SITC_2022_FINAL.pdf ## Summary Meredith S. Pelster, Michael Gordon, Tricia Wise-Draper, Jong Chul Park, Wade T. Iams, Julia J. Jennings, Nathan Miselis, Rui-Ru Ji, Scott Loughhead, Ricardo Zwirtes, Howard Bernstein, Armon Sharei, Antonio Jimeno, Sarah Cannon ## Publication text E Addressable Patient Population (%) ### Sqz-pbmc- ### Hpv SQZ-eAPC- ### Hpv 0 4 8 12 16 20 24 Hours Max Presentation (%) SQZ-PBMC-HPV SQZ-eAPC-HPV B IFNγ+CD45RO+ (% of CD3+CD8+) ### Sqz-pbmc- ### Cmv SQZ-eAPC- ### Cmv D Figure 3: SQZ-eAPC-HPV is an improved SQZ® clinical therapeutic candidate. A. SQZ® eAPC is an HLA agnostic drug product with a broader antigen repertoire, potentially increasing the addressable patient population by 2-3x. B. Preclinically, duration of presentation of HPV16 antigens is longer lasting with SQZ® eAPC compared to the SQZ® PBMC clinical therapeutic candidate. C. In humanized mice treated with SQZ® PBMC or SQZ® eAPC, SQZ® eAPC elicits a greater CD8+ T cell response. D. The addition of mRNAs encoding for signals 2 or 3 in SQZ® eAPC enhances T cells responses compared to the CpG maturation used to stimulate signal 2 in SQZ® PBMC. E. A table summarizing the key similarities and differences between the SQZ® PBMC-derived therapeutic candidates. SQZ® eAPC Enhancements C COMMANDER-001: A Phase 1/2, First-in-Human, Multicenter, Open-Label Study of SQZ-eAPC-HPV as Monotherapy and in Combination with Pembrolizumab in Patients with HPV16+ Recurrent, Locally Advanced, or Metastatic Solid Tumors (Trial in Progress) Meredith S. Pelster, Michael Gordon, Tricia Wise-Draper, Jong Chul Park, Wade T. Iams, Julia J. Jennings, Nathan Miselis, Rui-Ru Ji, Scott Loughhead, Ricardo Zwirtes, Howard Bernstein, Armon Sharei, Antonio Jimeno, Sarah Cannon Research Institute at Tennessee Oncology (Nashville, TN), HonorHealth Thompson Peak Medical Center (Scottsdale, AZ), University of Cincinnati Medical Center (Cincinnati, OH), Massachusetts General Hospital (Boston, MA), Vanderbilt University Medical Center (Nashville, TN), SQZ Biotechnologies (Watertown, MA), University of Colorado Cancer Center (Aurora, CO) ### Background - Antigen-specific CD8+ T cells are critical for mounting a potent immune response against tumors. Creation of T cell responses requires 3 key signals from antigen presenting cells (APCs) (Figure 1B): - Signal 1. the peptide-MHC complex binding to the T cell receptor - Signal 2. costimulatory molecules that bind to T cell stimulatory domains, and - Signal 3. inflammatory cytokines binding to receptors on T cells. - To create enhanced APCs (eAPCs) from peripheral blood mononuclear cells (PBMCs), Cell Squeeze® technology is used to deliver mRNAs encoding HPV16 E6 and E7 antigens (signal 1), CD86 (signal 2), and membrane-bound IL-2 and IL-12 cytokines (signal 3) (Figure 1). - Co-localizing signal 2 and 3 molecules on the eAPC surface potentiates T cell responses in in vitro human and in vivo humanized mouse models when compared to antigen alone. Clinically, this may enable more potent T cell stimulation and limit off-target effects from systemic exposure to signal 2 and 3 (Figure 2). - SQZ-eAPC-HPV is an enhanced SQZ® clinical therapeutic candidate, with no HLA restrictions, that leverages the clinical and manufacturing experience of the SQZ-PBMC-HPV product (Figure 3). This approach may potentially enable rapid implementation across other tumor types as it facilitates exchange of mRNA to encode for other antigens or T cell activation signals. ### Summary SQZ-PBMC-HPV SQZ-eAPC-HPV Differentiation Cell Type PBMC PBMC N/A Delivery material E6/E7 synthetic long peptide E6, E7, CD86, mbIL-2, and mbIL-12 mRNA More epitopes, longer duration of presentation, signal 2&3 Maturation 4 hr CpG incubation None Improved yield and shorter process time Anticipated T cell response HLA-A*02 restricted CD8+ T cell response HLA agnostic CD8+ T cell response. Potential for CD4 T cell response Broader, better stimulated T cell response across HLA types Sites of Priming Spleen and lymph Nndes Spleen and lymph nodes N/A Figure 1: Cell Squeeze® technology and antigen presentation approach. A. Peripheral blood mononuclear cells (PBMCs) are collected from the patient and squeezed with mRNA encoding for full length E6 and E7 proteins, CD86, membrane bound IL-2 and membrane bound IL-12, resulting in SQZ-eAPC-HPV. SQZ-eAPC-HPV is intravenously administered to the patient. SQZ-eAPC-HPV cells then migrate to the lymphoid organs where they are designed to activate CD8 T cells. B. mRNA transcripts encoding for full length E6 and E7 proteins, CD86, membrane bound IL-2 and membrane bound IL-12 are introduced into the cytosol of PBMCs using Cell Squeeze® technology. After IV administration of SQZ-eAPC-HPV, the mRNAs are expected to be translated resulting in signal 1, 2, and 3 activation and ultimately activation of HPV16 specific CD8 cells. Cell Squeeze® Technology and SQZ-eAPC-HPV A SQZ-eAPC-HPV Overview B PBMCs + mRNAs Cell Squeeze ® SQZ® eAPCs Lymph Node Spleen Tumor Figure 6: Collection to release for a patient. Eligible patients will undergo a single leukapheresis. In our GMP compliant manufacturing process, patient cells are processed in less than 24 hours to generate cryopreserved drug product. The time from leukapheresis to product release for the 1st administration is approximately one week. Patients do not require a conditioning regimen before the 1st administration; SQZ-eAPC-HPV is administered outpatient after the first dose. Leukapheresis SQZ Process <24-hours QC and Batch Release Administration to Patient SQZ-eAPC-HPV Manufacturing and Patient Experience - COMMANDER-001 (NCT05357898) leverages clinical and manufacturing experience from SQZ- PBMC-HPV-101 (NCT04084951), in which an unconfirmed partial response was observed in a patient receiving SQZ-PBMC-HPV monotherapy at the recommended phase 2 dose. - COMMANDER-001 is open for enrollment to patients with HPV16+ recurrent, locally advanced or metastatic solid tumors and includes a Monotherapy Dose Escalation Phase and a Combination Safety Phase with pembrolizumab (Figure 4). The study is being conducted at sites in the United States (Figure 5). - Eligible diseases are all HPV16 driven cancers (including anal, cervical, head and neck, penile, vaginal, and vulvar). - Patients will receive SQZ-eAPC-HPV q3w for up to 1 year or until available autologous drug product is exhausted. - Eligible patients will undergo a single leukapheresis collection at the study site. (Figure 6). - Treatment does not require a preconditioning regimen, e.g. immuno- or myeloablative regimen. - Dose limiting toxicity (DLT) period is 28 days for the monotherapy phase and 42 days for the combination phase. - Patients must have a lesion that can be biopsied at Screening and on study. Study Design Participating Study Centers Figure 5: Map of participating sites COMMANDER-001 is a phase 1/2 study being conducted in the United States. Three sites are currently open to enrollment (blue); more site are expected to open soon (orange). Open and Enrolling: Sarah Cannon Research Institute at Tennessee Oncology, Honor Health, University of Colorado; Sites Coming Soon: Massachusetts General Hospital, University of Cincinnati Medical Center, Vanderbilt University Medical Center Study Assessments - Safety and tolerability to identify the monotherapy recommended phase 2 dose (RP2D) and RP2D in combination with pembrolizumab - Preliminary evidence of antitumor activity of SQZ-eAPC-HPV monotherapy and in combination with pembrolizumab will be evaluated per RECIST 1.1 every 6 weeks for the first 2 scans, then every 8 weeks thereafter - Manufacturing feasibility of SQZ-eAPC-HPV - Exploratory endpoints include the following: - Assess the pharmacokinetics of SQZ-eAPC-HPV - Characterization of CD8 cells in tumor and blood. - Potential mechanism of resistance - Cytokine responses - Other pharmacodynamic evaluations such as circulating cellfree HPV16 DNA levels in plasma ### Methods Figure 4: COMMANDER-001 Study Design DLT period = 42 days Recurrent or metastatic HPV-16+ cancer HLA agnostic ICI-naïve patients (≤1 prior lines) Part 2: Lead-in Phase (Requires DSMB approval) SQZ-eAPC-HPV RP2D + pembrolizumab 200 mg q3w SQZ-eAPC-HPV RP2D 6w Recurrent or metastatic HPV-16+ cancer HLA agnostic Platinum experienced CPI experience/offered Part 1: Monotherapy Phase (1A) and Combination Phase (1B) Safety and Tolerability Manufacturing Feasibility Efficacy (ORR) Biomarkers SQZ-eAPC-HPV 2.5 x106/kg q3w SQZ-eAPC-HPV 5.0 x106/kg q3w SQZ-eAPC-HPV RP2D q3w + pembrolizumab 200 mg q3w n = 6 to 12 BOIN SQZ-eAPC-HPV 0.5 x106/kg q3w SQZ-eAPC-HPV RP2D-1 q3w + pembrolizumab 200 mg q3w n = 6 to 12 BOIN Dose de-escalation if DLT >30% Safety and Tolerability Manufacturing Feasibility Efficacy (ORR) Biomarkers Inclusion Criteria Inclusion Criteria Objectives Objectives DLT period = 28 days DLT period = 42 days Part 1A: SQZ-eAPC-HPV monotherapy will be tested with at least 3 different dose levels to identify the recommended phase 2 dose (RP2D). Additional higher or lower dose cohorts may be opened. Part 1B: SQZ-eAPC-HPV RP2D is tested in combination with 200 mg pembrolizumab. Pembrolizumab will be given on Cycle 1 Day 8. In subsequent cycles, after SQZ-eAPC-HPV on Day 1 of each cycle. Part 2: Lead-in SQZ-eAPC-HPV RP2D is tested in combination with 200 mg pembrolizumab. SQZ-eAPC-HPV is given as a monotherapy for the first 2 cycles, then from Cycle 3 pembrolizumab will be given on Day 1 after SQZ-eAPC-HPV. ### A B Figure 2: SQZ® eAPCs are capable of expanding autologous CD8+ T cells. Cell Squeeze® processed PBMCs were co-cultured with donor matched unprocessed PBMCs that served as a source of reactive CD8+ T cells. Following a 5-day co-culture, cells were stimulated with antigen mRNA and evaluated via intracellular cytokine staining for IFNγ (A) and TNFα (B). Squeezing all 4 mRNAs into PBMCs resulted in a significant increase in IFNγ and TNFα levels compared to antigen mRNA alone or CD86+mbIL-2+mbIL-12 mRNAs alone. SQZ® eAPC Preclinical Data A Presented at SITC 2022, Nov 8-12, 2022 ### Acknowledgements We thank the patients, their families, and their caregivers for their time and their willingness to participate in this study. We also thank the investigators and the investigational site staff for their contributions to the study. ## Provenance Some publications reference SQZ Biotechnologies, a company Dr. Armon Sharei and colleagues previously founded. Portal is the next generation company leveraging Dr. Sharei's platform technology.