Proving the Concept: A Sampler of Early Stage Science at AACR 2025

More so than most cancer meetings, scientific presentations at the American Association for Cancer Research (AACR) offer a glimpse into the future. Here, the floor belongs to basic science, as well as “first in human” and “proof of concept” phase 1 trials that shed light on brand new treatment approaches. Below are a sampling of early stage newsmakers from this year’s meeting, held April 25-30, 2025, in Chicago, Illinois.

An Off-the-Shelf CAR NK Therapy for Fast-Moving Blood Cancers

For all its success, chimeric antigen receptor (CAR) T-cell therapy is not for everyone. Some B-cell malignancies are very heterogeneous, meaning their features vary enough from patient to patient that it’s hard to come up with a consistent therapeutic target. And for patients with acute myeloid leukemia, which progresses rapidly, there may not be enough time for the multi-week manufacturing process involved in conventional CAR T, which creates a therapy from an individual’s T cells.1

That’s why it’s welcome news that several patients with AML in this phase 1 trial (NCT06325748) experienced complete remission after treatment with SENTI-202, a first-in-class CAR NK cell therapy from Senti Bio that uses natural killer cells to create a very different kind of treatment—one that can be made with healthy donor cells and stored for use in others.

Results presented Sunday show involve 9 patients with relapsed or refractory AML treated with different doses of the therapy; of these, 7 were evaluable for overall response at the data cut-off. Additional data showed:2

• Patients 1 tested 2 doses and 2 schedules. Based on the data identified a recommended phase 2 dose and schedule as 1.5 x 109 CAR NK cells administered on Days 0,7, and 14 in 28-day cycles, after patients complete lymphodepleting chemotherapy.
• 2 of 3 patients achieved composite complete remission (cCR), and 5 of the 7 best overall response evaluable patients achieved 5 of the 7 best overall response evaluable patients achieved an overall response, consisting of cCR plus a morphologic leukemia-free state, which means there are no longer leukemic blasts in the blood marrow. Of these patients, 4 of 7 achieved cCR, and 3 achived CR with a full hematologic recovery; 1 had a CR with partial hematologic recovery.
• SENTI-202 was well-tolerated with no dose limiting toxicities and a maximum tolerated dose was not reached. The phase 1 study is still enrolling patients to confirm the recommended dose for phase 2.

Stephen Strickland, MD, MSCI | Image credit: TriStar Health

Presenter Stephen Strickland Jr MD, MSCI, director of leukemia research for Sarah Cannon Research Institute, described the unmet need that SENTI-202 addresses. “There is no single target that is uniformly expressed across heterogeneous AML cells, and many targets that are potentially targetable in AML are also expressed on healthy cells,” he said in a statement.1

Proof of Mechanism Seen in Study of Treatment That Targets CCR8+ Tregs

A phase 1b trial (NCT05635643) confirmed the mechanism of action for CHS-114, a selective, cytolytic anti-CCR8 antibody, as monotherapy and in combination with toripalimab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). The data were announced by Coherus Biosciences, which makes both CHS-114 and toripalimab (Loqtorz), an FDA-approved next-generation PD-1 inhibitor.

CHS-114, an afucosylated CCR8 monoclonal antibody, works by depleting CCR8, a chemokine receptor selectively expressed on tumor-infiltrating T cells, or Tregs. Untreated, CCR8+ Tregs suppress the immune system and allow tumors to progress. Tested in mouse models, CHS-114 prompts an immune response by activating other cells in the HNSCC tumor microenvironment, including dendritic cells.

Douglas Adkins, MD | Image credit: WashU Medicine

The current study, presented Monday, confirmed partial response in a heavily pretreated patient who did not respond to prior PD-1 therapy. Results showed more than 50% depletion of CCR8+ Tregs and an increase in CD8+ T cells, confirming the mechanism of action. Safety results were consistent with known data for toripalimab, company officials said in a statement.3

“One of the biggest challenges in oncology has been finding a treatment that depletes Treg cells and relieves immune suppression in the tumor without causing collateral autoimmune disease or affecting antitumor T cells,” said Douglas Adkins, MD, professor of medicine and director, Section of Head and Neck and Thyroid Medical Oncology, Division of Medical Oncology, Washington University School of Medicine.3 “These early clinical results are exactly what we’ve been hoping for and demonstrate CHS-114’s ability to remodel the tumor microenvironment in favor of anti-tumor activity.”

Adkins noted that the treatment approach is being studied in other solid tumor types. Company officials said results support ongoing evaluation of CHS-114 in combination with other therapies, including toripalimab.3

Proof of Concept Seen for ADC Targeting Extradomain-B Fibronectin

If a tumor’s blood supply allows it to grow, it makes sense to look for early signs that the blood supply is fueling cancer.

That’s the concept behind Pyxis Oncology’s lead therapeutic candidate, micvotabart pelidotin (MICVO). This first-in-concept antibody-drug conjugate (ADC) targets extradomain-B fibronectin (EDB+FN), a protein with features that are “rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumors,” according to a 2020 article by Lieverse et al.

Instead of binding to surface antigens on the tumor cell—the normal mechanism of ADCs—MIVCO works by targeting EDB+FN within the tumor-extracellular matrix (ECM). According to information from Pyxis, this can disrupt the process of feeding the tumor structure, while at the same time killing other cancerous cells.

Lara Sullivan, MD | Image credit: Pyxis Oncology

Data presented at AACR Monday included an evaluation of the ADC in an abstract that showed MICVO demonstrated broad anti-tumor activity across 10 solid tumor indications in patient-derived xenographs, which are models based on tissue responses to recently developed drugs. According to the company’s statement, results showed 45% of models demonstrated strong to very strong tumor growth inhibition, with only 25% of models showing no response (TGI<25%). Results showed strong activity in 9 out of 10 indications and that MICVO would be well tolerated.4

A second abstract showed that combining anti-PD-1 and a mouse analog of the ADC had more impressive anti-tumor efficacy that either treatment alone.5

"Our lead therapeutic candidate micvotabart pelidotin (MICVO) has shown remarkably sustained efficacy in tumor clearance and immune activation across multiple models in preclinical studies, supporting our hypothesis that by targeting EDB+FN and releasing a potent payload in the tumor extracellular matrix, MICVO can potentially destabilize the barrier protecting and feeding the tumor structure while killing other tumor cells,” Pyxis President and CEO Lara Sullivan, MD, said in a statement.6

References

1. Off-the-shelf natural killer cell therapy with logic gates elicits complete remissins in relapsed or refractory blood cancers. News Release. American Association for Cancer Research. April 27, 2025. Accessed April 28, 2025. https://www.aacr.org/about-the-aacr/newsroom/news-releases/off-the-shelf-car-natural-killer-cell-therapy-with-logic-gates-elicits-complete-remissions-in-relapsed-or-refractory-blood-cancers/
2. Senti Bio’s SENTI-202, a first-in-class, off-the-shelf logic gated selective CD33 OR FLT3 NOT EMCN CAR NK cell therapy, demonstrates positive preliminary clinical results in the treatment of patients with R/R AML. News release. Senti Bio. April 27, 2025. Accessed April 28, 2025. https://investors.sentibio.com/news-releases/news-release-details/senti-bios-senti-202-first-class-shelf-logic-gated-selective
3. Coherus presents promising early clinical data from phase 1 dose expansion study of CHS-114 in patients with recurrent/metastatic head and neck squamous cell carcinoma at AACR 2025. News release. Coherus Biosciences. April 28, 2025. Accessed April 28, 2025. https://investors.coherus.com/news-releases/news-release-details/coherus-presents-promising-early-clinical-data-phase-1-dose
4. Facklam A, Trickett J, Lewandowski S, et al. Evaluation of PYX-201, an EDB+FN-targeting ADC, in a comprehensive PDX mini-trial study enables identification of gene signatures associated with anti-tumor activity. Presented at: American Association for Cancer Research 2025 Annual Meeting, April 25-30, 2025; Chicago, IL. Abstract 3120.
5. Rodriguez AB, Facklam A, Iovino M, et al. The combination of anti-PD1 and a mouse analog of PYX-201, an antibody-drug conjugate targeting the extra-domain B splice variant of fibronectin (EDB+FN), shows greater anti-tumor efficacy than either treatment alone. Presented at: American Association for Cancer Research 2025 Annual Meeting, April 25-30, 2025; Chicago, IL. Abstract 3137.
6. Pyxis Oncology presents promising preclinical results providing proof of mechanism of micvotabart pelidotin, the first-in-concept extracellular-targeting ADC. News release. Pyxis Oncology. Accessed April 28, 2025. https://ir.pyxisoncology.com/news-releases/news-release-details/pyxis-oncology-presents-promising-preclinical-results-providing