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The benefits of limiting dual antiplatelet therapy (DAPT) to a short course after PCI for acute coronary syndromes vary depending on the type of monotherapy used afterward, according to a new network meta-analysis.

Among more than 45,000 patients enrolled in 23 international studies, P2Y12 inhibitor monotherapy reduced both net adverse clinical events (NACE) and any bleeding compared with aspirin monotherapy. Additionally, compared with standard DAPT, only P2Y12 inhibitor monotherapy reduced both NACE and any bleeding, whereas aspirin did neither. Notably, the analysis showed no significant difference in NACE for short DAPT overall compared with standard DAPT.

The study shows that “short DAPT, in general, is a good option for patients with acute coronary syndromes if they don’t have excess thrombotic risk,” senior author Davide Capodanno, MD, PhD (University of Catania, Italy), told TCTMD. But one potential reason why the study didn’t show an overall benefit with less than 12 months of DAPT in this population “is because of the aspirin monotherapy after DAPT,” he added. “If we could continue the P2Y12 inhibitor monotherapy, that would be better.”

The analysis can’t compare to a randomized trial in this space—something Capodanno says is needed for ACS patients, who are currently treated with a “one-size-fits-all” strategy of 12-month DAPT—but it provides further rationale for one. “Within this population, there are patients who are at high bleeding risk and they have different combinations of thrombotic and bleeding risk, so it’s likely that we need to personalize in this population, specifically,” he said.

It’s likely that we need to personalize in this population. Davide Capodanno

Commenting for TCTMD, Marco Valgimigli, MD, PhD (Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland), agreed that the results suggest using P2Y12 inhibitor monotherapy instead of aspirin when a short course of DAPT is selected in this population. “However, I am not 100% sure the results that the authors are coming out with are the real ones,” he added as a caveat. “I think the P2Y12 inhibitor should be preferred because of the lower risk of subsequent NACE, not because of a clear bleeding advantage, which has never been reported by direct comparisons.”

The findings were published in the August 11, 2025, issue of JACC: Cardiovascular Interventions with Claudio Laudani, MD (University of Catania), as the first author.

Fewer NACE, Less Bleeding

For the meta-analysis, the researchers included 45,394 patients (51,568 patient-years; mean age 63 years; 23% women) from 23 trials with median DAPT durations of 4.8 and 2.2 months in those studying aspirin (n = 14) and P2Y12 inhibitor monotherapy (n = 9), respectively.

The risk of NACE was lower with P2Y12 inhibitor monotherapy compared with standard DAPT (incidence rate ratio [IRR] 0.78; 95% CI 0.64-0.95), but this was not seen with aspirin monotherapy versus standard DAPT (IRR 1.03; 95% CI 0.89-1.18; P = 0.026 for interaction). The findings were similar when looking at any bleeding for P2Y12 inhibitor monotherapy (IRR 0.56; 95% CI 0.46-0.67)—where there was also a significant reduction in major bleeding—compared with aspirin alone (IRR 0.84; 95% CI 0.66-1.06; P = 0.008 for interaction).

In a pooled analysis, the researchers found only a nonsignificant NACE reduction for short DAPT overall compared with standard DAPT. However, there were significant drops in both any and major bleeding with less than 12 months of DAPT.

In an indirect comparison, P2Y12 inhibitor monotherapy significantly reduced the risk of both NACE (IRR 0.77; 95% CI 0.62-0.95) and any bleeding (IRR 0.68; 95% CI 0.48-0.95) compared with aspirin monotherapy.

“Now it’s time for the comparison of monotherapies,” Capodanno said, noting that both SMART-CHOICE 3 and HOST-EXAM have compared clopidogrel and aspirin, but only in the “remote” period after PCI when the overall thrombotic risk is lower for patients. “What would be nice is to have a trial of P2Y12 inhibitor monotherapy versus aspirin for 3 to 6 months in patients with acute coronary syndromes to see whether there is, of course, a benefit of P2Y12 inhibitor monotherapy versus aspirin as well,” he suggested. “This is a kind of design that could clarify finally whether this is really a strategy that deserves better recommendation as compared with the standard of care.”

Valgimilgi, too, said the field needs a “direct comparison” of aspirin versus P2Y12 inhibitor monotherapy after DAPT discontinuation. “And we need to convince the people that the short DAPT regimen is the way forward,” he urged. “This is something I would like to emphasize. Whatever the type of monotherapy you’re going to choose, you have to go for a short DAPT regimen.”

Whatever the type of monotherapy you’re going to choose, you have to go for a short DAPT regimen. Marco Valgimigli

In an accompanying editorial, Giuseppe Gargiulo, MD, PhD (Federico II University of Naples, Naples, Italy), and colleagues write that “the actual superiority of short DAPT compared with standard DAPT in ACS, and even more the superiority of P2Y12 inhibitor monotherapy compared with aspirin monotherapy, should be interpreted with caution.”

Still, they continue, “we agree with the investigators’ conclusion that this meta-analysis can be useful for clinicians and future guidelines on the relative merits of the available antiplatelet monotherapy strategies, allowing a personalized approach depending on the ischemic and bleeding risk balance.”

Over the past 20 years, a class of cancer drugs called CD40 agonist antibodies have shown great promise—and induced great disappointment. While effective at activating the immune system to kill cancer cells in animal models, the drugs had limited impact on patients in clinical trials and caused dangerously systemic inflammatory responses, low platelet counts, and liver toxicity, among other adverse reactions—even at a low dose.

But in 2018, the lab of Rockefeller University’s Jeffrey V. Ravetch demonstrated it could engineer an enhanced CD40 agonist antibody so that it improved its efficacy and could be administered in a manner to limit serious side effects. The findings came from research on mice, genetically engineered to mimic the pathways relevant in humans. The next step was to have a clinical trial to see the drug’s impact on cancer patients.

Now the results from the phase 1 clinical trial of the drug, dubbed 2141-V11, have been published in Cancer Cell. Of 12 patients, six patients saw their tumors shrink, including two who saw them disappear completely.

“Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable,” says first author Juan Osorio, a visiting assistant professor in Ravetch’s Leonard Wagner Laboratory of Molecular Genetics and Immunology and a medical oncologist at Memorial Sloan Kettering Cancer Center.

Notably, the effect wasn’t limited to tumors that were injected with the drug; tumors elsewhere in the body either got smaller or were destroyed by immune cells.

“This effect—where you inject locally but see a systemic response—that’s not something seen very often in any clinical treatment,” Ravetch notes. “It’s another very dramatic and unexpected result from our trial.”

Engineering enhancements

CD40 is a cell surface receptor and member of the tumor necrosis factor (TNF) receptor superfamily, proteins that are largely expressed by immune cells. When triggered, CD40 prompts the rest of immune system to spring into action, promoting antitumor immunity and developing tumor-specific T cell responses.

In 2018, Ravetch’s lab—which has been supported in this line of research by Rockefeller’s Therapeutic Development Fund, founded by trustee Julian Robertson and continued by the Black Family Foundation—engineered 2141-V11, a CD40 antibody that binds tightly to human CD40 receptors and is modified to enhance its crosslinking by also engaging a specific Fc receptor. It proved to be 10 times more powerful in its capacity to elicit an antitumor immune response.

They then changed how they administered the drug. The long-time approach had been to give it intravenously. But CD40 receptors are widespread, so too many non-cancerous cells pick it up, leading to the well-known toxic side effects. Instead, they injected the drug directly into tumors.

“When we did that, we saw only mild toxicity,” Ravetch says.

Those findings became the basis of the phase 1 clinical trial described in the current study, which aimed to determine a starting clinical dose of the drug and better understand the mechanisms underlying its effectiveness.

Inducing remission

The trial included 12 patients representing myriad metastatic cancer types: melanoma, renal cell carcinoma, and different types of breast cancer. Of those 12, none suffered the serious side effects seen with other CD40 drugs. Six experienced systemic tumor reduction, of which two had a complete response—meaning their cancer disappeared entirely.

The two patients who experienced complete remission had melanoma and breast cancer, respectively—both notoriously aggressive and recurring.

“The melanoma patient had dozens of metastatic tumors on her leg and foot, and we injected just one tumor up on her thigh,” Ravetch says. “After multiple injections of that one tumor, all the other tumors disappeared. The same thing happened in the patient with metastatic breast cancer, who also had tumors in her skin, liver, and lung. And even though we only injected the skin tumor, we saw all the tumors disappear.”

Tissue samples from the tumor sites revealed the immune activity that the drug stimulated. “We were quite surprised to see that the tumors became full of immune cells—including different types of dendritic cells, T cells, and mature B cells—that formed aggregates resembling something like a lymph node,” Osorio says. “The drug creates an immune microenvironment within the tumor, and essentially replaces the tumor with these tertiary lymphoid structures.”

The presence of tertiary lymphoid structures (TLS) is associated with improved prognosis and response to immunotherapy, Osorio notes.

They also found TLS in the tumors they didn’t inject. “Once the immune system identifies the cancer cells, immune cells migrate to the non-injected tumor sites,” he says.

Improving immunotherapy

The findings have sparked a number of other clinical trials that the Ravetch lab is currently collaborating on with researchers at Memorial Sloan Kettering and Duke University. Now in either phase 1 or phase 2 study, the trials are investigating 2141-V11’s effect on specific cancers, including bladder cancer, prostate cancer, and glioblastoma—all aggressive and hard to treat. Collectively, nearly 200 people are enrolled in the studies.

These studies will help to illuminate why some patients respond to 2141-V11 and others do not—and how to potentially change that.

For example, the two patients in the clinical trial whose cancer disappeared both had a high clonality of T cells—key cancer-cell killers—when they began the study. “This suggests there are some requirements from the immune system in order for this drug to work, and we’re in the process of dissecting these characteristics in more granular detail in these larger studies.”

“As a general rule, only 25 to 30% of patients will respond to immunotherapy, so the biggest challenge in the field is to try to determine which patients will benefit from it. What are the indicators or predictors of response? And how can we convert non-responders into responders?”

Reference: Osorio JC, Knorr DA, Weitzenfeld P, et al. Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer. Cancer Cell. doi: 10.1016/j.ccell.2025.07.013

 

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