A Seamless Phase 1/2 Study to Evaluate the Safety and Efficacy of A2B395, an Allogeneic Logic-gated Tmod™ CAR T, in Heterozygous HLA-A*02 Adults With Recurrent Unresectable, Locally Advanced, or Metastatic Solid Tumors That Express EGFR and Have Lost HLA-A*02 Expression

The goal of this study is to test A2B395, an allogeneic logic-gated Tmod™ CAR T-cell product in subjects with solid tumors including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), renal cell carcinoma (RCC) and other solid tumors that express EGFR and have lost HLA-A\*02 expression. The main questions this study aims to answer are: * Phase 1: What is the recommended dose of A2B395 that is safe for patients * Phase 2: Does the recommended dose of A2B395 kill the solid tumor cells and protect the patient's healthy cells Participants will be required to perform study procedures and assessments, and will also receive the following study treatments: * Enrollment in BASECAMP-1 (NCT04981119) * Preconditioning lymphodepletion (PCLD) regimen * A2B395 Tmod CAR T cells at the assigned dose

More details:

This is a seamless phase 1/2, multi-center, open-label study that enrolls adults with recurrent unresectable, locally advanced, or metastatic (considered non-curative) CRC, NSCLC, HNSCC, TNBC, RCC, or other solid tumors with EGFR expression. Subjects must be germline HLA-A\*02 heterozygous, with tumors that express EGFR and have lost HLA-A\*02 expression. The purpose of Phase 1 of this study is to determine the safety and the optimal dose of A2B395 (after PCLD) in participants with solid tumor disease. The purpose of Phase 2 of this study is to determine the further safety and efficacy (how well it treats the solid tumor disease) of A2B395. The treatment available for these cancers and other solid tumors can be toxic, debilitating, and fatal. In the recurrent unresectable, locally advanced, or metastatic setting, the intent of standard of care treatment is typically palliative rather than curative, and has not changed significantly in several decades. A2 Bio hypothesizes that A2B395 Tmod CAR T-cell therapy will enable the killing of tumor target cells (those cells that express EGFR and have loss of heterozygosity \[LOH\] for the HLA-A\*02 protein). Additionally, normal healthy cells that maintain HLA-A\*02 expression and co-express EGFR (eg, skin tissue) will not be targeted due to the blocker portion of the Tmod CAR T cell that acts as a self-regulated safety switch that protects normal tissue from damage. Furthermore, the blocker portion of the Tmod CAR T cell will act as a safety switch to protect normal tissue from graft versus host disease (GvHD) that could be caused by an allogeneic CAR T cell. A2 Bio intends this to provide a wider therapeutic safety window compared to previous solid tumor targeting therapies. This hypothesis will be explored in the study. Participants for this study must enroll and have confirmation of LOH in the pre-screening BASECAMP-1 study (NCT04981119). Upon disease progression the participant may screen for this study (DENALI-1). There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to DENALI-1 based on their own disease course.

Overview

A2B395 (A2B-395) is an investigational, donor-derived CAR T-cell therapy being studied in the phase 1/2 DENALI-1 trial for previously treated, EGFR-expressing solid tumors that have lost HLA-A02 expression. The human results available so far are early, company-reported findings*, not a peer-reviewed efficacy analysis. (mayo.edu)

Mechanism of action

A2B395 uses an EGFR-targeting activator intended to attack tumor cells and an HLA-A02-targeting blocker intended to restrain activity against healthy cells that retain HLA-A02. Trial eligibility therefore requires evidence of HLA-A*02 loss in the tumor. (a2bio.com)

Efficacy

As of August 1, 2026, 10 patients had received A2B395 and nine were evaluable for response. The company reported one complete response (anal cancer), one confirmed partial response (head and neck cancer), five cases of stable disease, and two cases of progressive disease. That is 2 responses among 9 evaluable patients (22%). The small, nonrandomized study cannot establish how well the treatment works across cancer types. (a2bio.com)

Safety

Among the 10 treated patients, the company reported two cases of grade 1–2 cytokine release syndrome, both resolved, and transient low blood-cell counts after lymphodepleting chemotherapy. It reported no dose-limiting toxicities, graft-versus-host disease, neurotoxicity syndrome, or treatment-related deaths at that cutoff. Longer follow-up and more patients are needed to characterize safety. (a2bio.com)

Further reading

• DENALI-1 study-design poster (ASCO 2025)
• DENALI-1 trial description (Mayo Clinic)
• Company-reported early clinical findings (September 15, 2026)

Last updated: Sep 2026

Inclusion Criteria:

Key Inclusion Criteria:

1. Appropriately enrolled in the BASECAMP-1 A2 Biotherapeutics, Inc. study, with tissue demonstrating LOH of HLA-A\*02 by NGS (whenever possible from the primary site).

2. Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, HNSCC, TNBC, RCC, or other solid tumors with EGFR expression. Measurable disease is required with lesions of ≥1.0 cm by CT.

3. Received previous required therapy for the appropriate solid tumor disease as described in the protocol

4. Has adequate organ function as described in the protocol

5. ECOG performance status of 0 to 1

6. Life expectancy of ≥3 months

7. Willing to comply with study schedule of assessments including long-term safety follow-up

Key Exclusion Criteria:

1. Has disease that is suitable for local therapy or able to receive standard of care therapy that is therapeutic and not palliative

2. Prior allogeneic stem cell transplant

3. Prior solid organ transplant

4. Cancer therapy within 3 weeks or 3 half lives of A2B395 infusion

5. Radiotherapy within 28 days of A2B395 infusion

6. Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months

7. Any new symptomatic pulmonary embolism (PE) or a deep vein thrombosis (DVT) within 3 months of enrollment. Therapeutic dosing of anticoagulants is allowed for history of PE or DVT if greater than 3 months from time of enrollment, and adequately treated

8. History of interstitial lung disease including drug-induced interstitial lung disease and radiation pneumonitis that requires treatment with prolonged steroids or other immune suppressive agents within 1 year

9. Requires supplemental home oxygen

10. Females of childbearing potential who are pregnant or breastfeeding

11. Subjects, both male and female, of childbearing potential who are not willing to practice birth control from the time of consent through 6 months post infusion of A2B395