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A new study sheds light on why many patients with advanced skin cancer fail to benefit from immune checkpoint blockade (ICB) therapies and suggests a potential fix using a drug already approved for blood cancers.

Published in Nature Immunology, the research identifies a biological mechanism that helps explain resistance to ICB drugs such as anti-PD-1 antibodies, a mainstay in treating melanoma and other solid tumors. Although these therapies can produce durable responses, more than 60% of patients see no benefit, while experiencing high toxicity side effects and the financial cost without any improvement.

Scientists at Newcastle University in Newcastle upon Tyne, United Kingdom, found that resistance may stem from the unintended effects of ICB therapy on a type of immune cell called regulatory T cells, or Tregs. These cells normally help keep immune responses in check. But when PD-1 is blocked on Tregs, it causes them to become more suppressive, allowing tumors to continue growing despite treatment.

To study this, the researchers engineered a mouse model where PD-1 was removed only from Treg cells. In these animals, tumor growth accelerated. A deeper look revealed that this PD-1 disruption drove up levels of CD30, a surface protein associated with immune suppression. When researchers blocked CD30 in addition to PD-1, the tumors became more vulnerable to immune attack.

That finding points to a possible treatment strategy: combining PD-1 inhibitors with CD30-targeting drugs. One such drug, Adcetris (brentuximab vedotin), is already approved for lymphoma and could be repurposed. In support of that idea, an ongoing Phase II trial is testing this combination in patients with metastatic melanoma who didn’t respond to standard checkpoint inhibitors. Preliminary data show a median survival of 24%.

“By simply adding anti-CD30 for these patients, we can improve their response to cancer and avoid costly delays,” said Shoba Amarnath, Ph.D., reader in immune regulation at Newcastle University, who led the research, in a news release. “Although our work was limited to skin cancer, we believe this new combination treatment will also benefit patients with lung, bowel, pancreatic and other solid cancers who are currently not responding to treatment with ICB monotherapy.”

Checkpoint inhibitors have transformed care for patients with advanced skin cancer. A study published last year by Dana-Farber Cancer Institute found that about half of patients with metastatic melanoma who received a combination of immunotherapies were alive and cancer-free 10 years after treatment—compared to a median survival of just six and a half months before these drugs were available.

The Newcastle study also adds to the understanding of how Tregs behave in the tumor microenvironment. The research team found that Tregs in ICB-treated tumors begin to resemble stem cells and cluster near tumor cells, forming immunosuppressive hubs that protect the cancer from immune attack. This behavior may help explain why simply boosting T cell activity with checkpoint inhibitors doesn’t work for many patients.

The researchers also wrote that CD30 levels rose in human Tregs after exposure to PD-1 blockade, but not in untreated tumor environments. This suggests that CD30 activation is potentially a side effect of the therapy itself, one that could be anticipated and countered with combination treatment.

“We are very excited to find all these new aspects in ICB resistance biology,” Amarnath said. “We believe targeting immune molecules and tumor growth proteins will significantly enhance the efficacy of ICB in solid cancers.”

Before Q2, HCPLive spoke with Steve Levine, MD, from Compass Pathways, for a Q1 recap and a look ahead at what was to come in psychiatry. Now that the quarter has wrapped, we’re revisiting those expectations.

Back in April, Levine highlighted 2 key studies to watch: Compass Pathways’ topline results for COMP360 psilocybin and Beckley Psychtech’s intranasal 5-MeO-DMT (BPL-003), both for TRD. Compass delivered on June 23, publishing phase 3 data from COMP005. A single 25 mg dose of COMP360 led to a significant reduction in depression severity at 6 weeks.

Beckley followed with their phase 2b data on July 1. BPL-003 met its primary and secondary endpoints, showing rapid, robust antidepressant effects after a single dose.1 Patients on 8 mg and 12 mg had meaningful symptom reduction by week 8, and most were ready for discharge within 90 minutes, fitting well within the 2-hour in-clinic model.

Along with the promising COMP360 data, this recap spotlights the unsuccessful phase 3 ARISE trial for xanomeline-trospium (Cobenfy) as an adjunctive schizophrenia treatment, an interview with John Kane, MD, on promising LB-102 data, and new podcast episodes of Medical Ethics Unpacked and the Gus Alva Perspective.

FDA Updates

FDA Officially Eliminates Clozapine REMS

On June 13, 2025, the US Food and Drug Administration (FDA) officially eliminated the clozapine REMS program to improve access to this effective treatment for schizophrenia. Although monitoring for severe neutropenia remains recommended, prescribers now have sole responsibility for determining clozapine’s use. In response, the Schizophrenia & Psychosis Action Alliance and American Association of Psychiatric Pharmacists are launching A New Era in Clozapine Management this fall to support safe, stigma-free prescribing.

What’s Moving in the Pipeline

Compass Pathways’ COMP360 Psilocybin Shows Benefit in Phase 3 TRD Trial

Compass Pathways announced positive topline results from its pivotal phase 3 COMP005 trial on June 23. A single 25 mg dose of COMP360 led to significant reductions in depression severity at 6 weeks among patients with TRD, meeting the primary endpoint. No major safety concerns were reported. The company plans to share 26-week follow-up data once its companion trial (COMP006) progresses.

Cobenfy Falls Short in Phase 3 ARISE Trial as Adjunctive Schizophrenia Therapy

In the phase 3 ARISE trial, xanomeline and trospium chloride (Cobenfy) did not achieve a statistically significant benefit as an adjunctive schizophrenia treatment. The 6-week study showed only a modest 2-point PANSS score difference versus placebo. However, subgroup analysis suggested Cobenfy may be more effective when paired with non-risperidone antipsychotics. Despite the missed endpoint, the safety profile remained favorable, and further research is encouraged.

Interview With John Kane, MD, on LB-102

LB-102 Significantly Improves Disease Severity in Acute Schizophrenia, with John Kane, MD

LB-102, a novel oral benzamide antipsychotic, demonstrated significant improvement in disease severity in the phase 2 NOVA trial. Doses of 50–100 mg led to meaningful CGI-S score reductions and positive effects on PANSS scores, with minimal weight gain and extrapyramidal symptoms. Lead investigator John Kane, MD, noted its potential to address unmet needs, particularly for negative symptoms and maintenance therapy.

Gus Alva Perspective

Launched May 16, 2025, The Gus Alva Perspective is a clinician-focused podcast hosted by psychiatrist Gus Alva, MD, medical director of ATP Research. With new episodes twice monthly, the show offers expert commentary on treatment advances and exclusive coverage leading up to the Southern California Psychiatry Meeting.

Featured Episodes:

The Gus Alva Perspective: SoCal Psych Preview—Schizophrenia Updates, with Jonathan Meyer, MD

The Gus Alva Perspective: SoCal Psych Preview—Tardive Dyskinesia, with Jonathan Meyer, MD

The Gus Alva Perspective: SoCal Psych Preview—Metabolic Revolution in Mood Disorders, with Roger McIntyre, MD

Medical Ethics Unpacked

Medical Ethics Unpacked: Shifting Vaccine Regulation and Policy, with Jason Schwartz, PhD

Jason Schwartz, PhD, of Yale, joins hosts Dominic Sisti, PhD, and Steve Levine, MD, to discuss the ethics of vaccine regulation. They examine how COVID-19 reshaped vaccine trust, amplified political divisions, and exposed vulnerabilities in public health infrastructure. The conversation addresses tensions between individual rights and collective health, misinformation’s impact, and the controversial replacement of ACIP members by HHS Secretary Robert F. Kennedy Jr.

Medical Ethics Unpacked: Unique Ethical Challenges of Psychedelic Therapies

Amy McGuire, JD, PhD, from Baylor College of Medicine, joins Sisti and Levine to explore the unique ethical issues in psychedelic therapy, particularly informed consent, cultural integration, and altered states of consciousness. The FDA’s recent rejection of MDMA-assisted therapy for PTSD has heightened debate over how to responsibly introduce these treatments into Western clinical practice.

References

atai Life Sciences and Beckley Psytech Announce Positive Topline Results from the Phase 2b Study of BPL-003 in Patients with Treatment-Resistant Depression. Beckley Psychtech. July 1, 2025. https://www.beckleypsytech.com/posts/atai-life-sciences-and-beckley-psytech-announce-positive-topline-results-from-the-phase-2b-study-of-bpl-003-in-patients-with-treatment-resistant-depression. Accessed July 1, 2025.

Researchers at the Korea Research Institute of Standards and Science (KRISS) have created a new nanomaterial that can simultaneously detect and treat cancer using multiple approaches. In laboratory tests with mice, the gold-iron particles enabled real-time tumor imaging while delivering targeted treatment through heat, chemical reactions and immune system activation. Published in the Chemical Engineering Journal, the study indicates these multifunctional particles have the potential to locate tumors, treat them at the optimal moment and help trigger immune responses against cancer cells.

The core of the KRISS research lies in the nanodisk’s gold-iron-gold sandwich structure, where each layer serves a distinct purpose. The outer gold layers enable heat-based cancer cell destruction when activated by laser light. Meanwhile, the iron core provides magnetic guidance and triggers chemical reactions that damage tumor cells through oxidation and ferroptosis. This structural design allows the particles to deliver three complementary therapies simultaneously. The combination promises to offer a significant advance over current nanomaterials that typically offer a single treatment modality.

“Unlike conventional nanomaterials, which are composed of a single element and perform only one function, the material developed in this study utilizes the combined properties of gold and iron to perform multiple functions,” said Dr. Lee Eun Sook, in a press release.

Photo-acoustic imaging in the mouse study demonstrated that “PA imaging using AuFeAuNDs as a robust contrast agent offers precise localization of tumor tissue and guidance for PTT.” The researchers noted in the paper that “the magnetic-targeted AuFeAuNDs not only eliminate tumor cells but also initiate ICD by releasing DAMPs in tumor-bearing mice, leading to the augmentation of cytotoxic T cells.”

In turn, this imaging capability promises to enable clinicians to monitor nanoparticle accumulation in real-time and determine optimal treatment timing, assuming the research proceeds to human trials. The study showed that the particles triggered “immunogenic cell death (ICD) by releasing damage-associated molecular patterns (DAMPs), thus stimulating an anti-tumor immune response.”

The KRISS breakthrough builds on extensive global research into multifunctional cancer nanoparticles. Georgia Tech and Emory researchers recently developed Janus cellular backpacks that insert into cell membranes while carrying therapeutic payloads. Other teams have explored gold-copper sulfide hybrids that combine NIR-II imaging with chemical therapy, while multiple groups are investigating metal-organic framework platforms for combined heat and chemical treatments. Despite these varied strategies, most rely on core-shell or surface-modified designs rather than the precise trilayer architecture achieved by KRISS through nanoimprint lithography. The KRISS approach may thus offer an advantage when it comes to stability and controlled therapeutic delivery.

Filed Under: Drug Discovery, Oncology