How Resting Immune Cells Could Be the Key to Fighting Prostate Cancer

In medicine, and especially in oncology, a powerful assumption often guides treatment strategy: More is better. More aggressive therapies and more frequent dosing are traditionally seen as the most direct path to attacking a disease and achieving a positive outcome. The goal is to keep constant pressure on the cancer, giving it no room to grow or recover.

However, a recent translational analysis of a clinical trial for an advanced prostate cancer drug, pasritamig (JNJ-78378343), has challenged this fundamental belief. The study (NCT04898634),² conducted in patients with metastatic castration-resistant prostate cancer (mCRPC), revealed a surprising and powerful lesson. It found that sometimes the most effective strategy isn't relentless attack, but rather giving the body’s own immune system a strategic break.¹

Less Frequent Dosing Led to Better Patient Responses

The primary and most surprising outcome of the pasritamig analysis was clear: Patients responded better to the drug when it was administered less frequently. The study compared intravenous (IV) dosing schedules for patients with mCRPC and found that an every-6-week (Q6W) schedule was clinically superior to an every-week (QW) or every-3-week (Q3W) schedule.

The data, measured by a significant drop in patients' prostate-specific antigen (PSA) cancer markers, illustrate a distinct advantage for the less frequent schedule across multiple time points:

• At any time: 44% of Q6W patients had a PSA50 response, compared with 33% of Q3W patients.
• Confirmed at 3 weeks: 35% of Q6W patients had a confirmed response, more than double the 17% of Q3W patients.
• Confirmed at 12 weeks: 33% of Q6W patients had a confirmed response, again nearly double the 17% of Q3W patients.

Based on these results and supporting translational data, the recommended phase 2 dose was established as:

• Step-up 1: 3.5 mg IV on day 1
• Step-up 2: 18 mg IV on day 8
• Target dose: 300 mg IV on day 15, then 300 mg IV every Q6W

The Immune System's Best Fighters Can Get Exhausted

The explanation for this paradoxical result lies in the biology of the immune system. Pasritamig is a T-cell engager, acting like a molecular bridge to connect T cells to cancer cells to ensure a targeted attack. The central hypothesis of the research was that giving the drug too often can backfire.

The study was framed by the modern understanding of T-cell exhaustion, which occurs under conditions of chronic antigen exposure, such as cancer.

• Progenitor exhausted T-cells: These cells are characterized by the expression of TCF1. They retain the ability to self-renew and can be reprogrammed to regain full effector function upon restimulation.
• Terminal exhausted T-cells: These cells have lost TCF1 expression. This differentiation is considered irreversible, resulting in a loss of proliferative potential and effector function. They are characterized by high expression of inhibitory receptors like PD-1, TIM3, and LAG3.

The goal of an effective T-cell–engaging therapy is to maintain a healthy pool of progenitor T cells while avoiding the push toward terminal exhaustion.

The analysis of patient peripheral blood mononuclear cells revealed that less frequent dosing with pasritamig drives a more productive and sustainable T-cell response.

• Mitigation of T-cell exhaustion: The Q6W dosing schedule was shown to limit T-cell exhaustion. It preserved a higher proportion of reprogrammable progenitor T-cells (TCF1+), which are critical for long-term antitumor immunity.
• Avoidance of overactivation: In contrast, more frequent dosing schedules (QW and Q3W) were associated with an increase in activated T cells that had lost TCF1 expression (CD69+ TCF1–). This phenotype represents a population on the path to terminal exhaustion.
• Reduction in cell death: The QW and Q3W cohorts showed evidence of increased activation-induced T-cell death, suggesting that continuous stimulation was leading to the premature elimination of activated T cells.

Rewriting the Rule Book for T-Cell Therapies

The findings from the pasritamig trial have implications that extend far beyond this single drug.

“As the mechanism of action of T-cell engagers is vastly different from currently available modalities, dose optimization should include analyses of immune parameters [health, status, immune system readiness, etc] as well as pharmacokinetics,” said Karen Autio, MD, Memorial Sloan Kettering Cancer Center, in a presentation of the analysis.

REFERENCES

1. Autio K, Schweizer MT, Shotts K, et al. Translational analyses of T-cell phenotypes and their association with clinical efficacy in the first-in-human (FIH) trial of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2385MO.

2. A study of JNJ-78278343, a T-cell-redirecting agent targeting human kallikrein 2 (KLK2), for advanced prostate cancer. ClinicalTrials.gov. Updated October 10, 2025. Accessed November 13, 2025. https://clinicaltrials.gov/study/NCT04898634