# A Phase I/II Trial Investigating Safety and Efficacy of Autologous T Cell Antigen-Coupler (TAC) T Cells Targeting HER2 in Relapsed or Refractory Solid Tumors (TACTIC-2).

**Authors:** Ecaterina E. Dumbrava, Daniel Olson, Benjamin L. Schlechter, Samuel Saibil, Donna Rill, Andreas G. Bader, Deyaa Adib, Michael Bishop  
**Institutions:** The University of Texas MD Anderson Cancer Center;  University of Chicago;  Dana Farber Cancer Center;  University Health Network Princess Margaret;  Triumvira Immunologics, Inc.

## BACKGROUND:

Despite recent therapeutic advances for patients with breast, colorectal, and gastroesophageal cancers with HER2 overexpression, there is still a significant unmet medical need for better treatment options for HER2-positive solid tumors, especially those with low or intermediate HER2 expression (1+ and 2+ by immunohistochemistry (IHC)). The T Cell Antigen-Coupler (TAC) technology is a novel way to genetically modify T cells and to redirect these T cells to target cancer antigens and to activate T cells naturally by co-opting the natural T cell Receptor (TCR).

## TAC SCIENCE

Key features of TAC Technology:

- TAC functions independently of MHC
- TAC requires endogenous TCR for T cell activation
- TAC incorporates the CD4 co-receptor and recruits the TCR complex, mimicking natural TCR activation

The TAC receptor interacts directly with the TCR-CD3 epsilon domain (1).

The TAC receptor then signals through the CD3-TCR complex (3).

The TAC receptor also binds directly to the tumor antigen, initiating the first step in T cell activation (2) which then leads to the clustering of TAC-TCR complexes required for full T cell activation.

This ultimately results in tumor cell lysis (4).

## PRECLINICAL DATA

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NRG mice (N=5) were subcutaneously inoculated with 2.5x10<sup>3</sup> OVCAR3 tumor cells. Tumors were allowed to engraft and grow to an average size of 100-200mm. Mice were then treated (2 doses 48hr apart) via tail vein injection, using a split dose of 1 million transduced HER2-TAC, HER2-CAR, or control T cells per dose.

## TACTIC-2 Study Design

### Phase I (Dose Escalation)

- Determine safety, MTD/RP2D, PK, Biomarkers Evaluation

### Phase II (Dose Expansion)

- HER2+ solid tumors (1+, 2+, 3+)  
- N~20 Defining RP2D  
- Prelim efficacy and expanded data for safety, PK, and biomarkers.

**Study Groups:**  
- 3+ HER2+ breast cancer: N~20 in 3L+  
- 2+ HER2+ solid tumors including breast cancer: N~10

| OBJECTIVES | ENDPOINTS |
| --- | --- |
| PRIMARY: To Evaluate the safety of TAC01-HER2 in subjects with HER2+ solid tumors | Incidence of Dose Limiting Toxicities(DLTs); Adverse events(AEs) and laboratory abnormalities |
| SECONDARY: To determine the MTD and RP2D for TAC01-HER2 | Incidence of DLTs |
| SECONDARY: To characterize the pharmacokinetic(PK) profile of TAC01-HER2 | Cmax,Tmax, and AUC of TAC01-HER2 cells; Duration of persistence of TAC01-HER2 cells |
| SECONDARY: To evaluate the efficacy of TAC01-HER2 | Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Version 1.1; Overall Response Rate (ORR); Duration of Response (DOR); Overall Survival (OS) |
| EXPLORATORY: Biomarker Studies to characterize T-cells and clinical outcomes |  |

## Key Inclusion:

- Eligible patients are ≥ 18 years with HER2-positive solid tumors (1+, 2+ or 3+ by IHC, regardless of amplification status) who progressed after at least two lines of systemic therapy.
- ECOG of 0/1 at screening
- Life expectancy of at least 12 weeks
- Adequate vascular access for leukapheresis
- Absolute Leukocyte Count (ALC) of ≥ 450/mcL

## Key Exclusion:

- Prior treatment with adoptive cell transfer of any kind including CAR-T cells and Gene Therapy,
- Receipt of a live vaccine, monoclonal antibody or radiation within 28 days of leukapheresis
- Chemotherapy or targeted small molecule therapy within 14 days prior to leukapheresis

## Study Assessments:

- Upon enrollment, patients will undergo leukapheresis to obtain T-cells for manufacture, some patients may receive bridging therapy prior to lymphodepletion chemotherapy (LDC).
- LDC will be administered and completed at least 24-48 hrs. prior to TAC01-HER2  
- Flu = 3 consecutive days at 30 mg/m<sup>2</sup>  
- Cy = 3 consecutive days at 300mg/m

- Tumor response assessments are performed at 4 weeks, then at months 3, 6, 9, 12, 18, and 24.
- After study completion, subjects are followed for survival and long-term safety for up to 15 years.

## Study Progress:

The TACTIC-2 study has completed enrollment of cohort #1. The study is registered with Clinicaltrials.gov (NCT04727151).

The study is currently recruiting patients with HER2 positive tumors at the following clinical sites:

- MD Anderson Cancer Center – Dr. Ecaterina E. Dumbrava
- Dana Farber Cancer Institute – Dr. Benjamin Schlechter
- The University of Chicago – Dr. Michael Bishop and Dr. Daniel Olson
- Princess Margaret, Toronto - Dr. Samuel Saibil

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## AACR 2022 Abstract #: CT247