Detailing the Potential Benefit of Intratumoral Therapies in Lung Cancer

Dr. Jared Weiss walks patients through the therapeutic potential viability of intratumoral therapies among those with lung cancer.

JNJ-1900 (NBTXR3) is a novel intratumoral radioenhancer, activated by radiation therapy, which is being investigated in phase 1 clinical research for patients with lung cancer, according to Dr. Jared Weiss, who went on to explain that the therapeutic is designed to minimize damage to surrounding healthy lung tissue while amplifying the local effect of radiation therapy.

This research remains vital because lung cancer is still one of the leading causes of cancer death world-wide, increasing the need for new treatment options. In order to address this unmet need, intratumoral therapies are continuing to be investigated. They have the potential to minimize toxicity early on during treatment through higher concentrations of localized therapy, according to a news release detailing the investigation from Johnson and Johnson.

“I'm personally very intrigued by recent data exploring why immunotherapy often fails when combined concurrently with radiation. Most famously, these failures are observed in head and neck cancer, another area of my interest,” Weiss explained in a Q&A-style interview with CURE.

“We have multiple trials showing that adding immunotherapy at the same time as radiation doesn't seem to help,” he continued.

Weiss, section chief of Thoracic and Head/Neck Oncology at the UNC Lineberger Comprehensive Cancer Center, located in Chapel Hill, North Carolina, sat down to discuss the investigation of JNJ-1900, expanding on the logistical and clinical challenges of intratumoral delivery in lung cancer, as well as the safety of the therapeutic.

Weiss is also the professor of Medicine in the Department of Medicine, Division of Oncology, at the UNC School of Medicine.

CURE: A key concern with radiotherapy is damage to surrounding healthy lung tissue. How does JNJ-1900 help mitigate this risk, and what are the preliminary safety and feasibility signals emerging from the trial?

Weiss: The product is a half-million nanoparticle that you inject into the tumor, specifically into the area you plan to radiate. The units of traditional radiation are called photons. What 1900 does is, for every one photon it absorbs, it releases nine electrons. Electrons are also a form of radiation, and critically, they don't travel very far, which provides its specificity. It's very, very focal in that way.

Intratumoral therapies are gaining attention for their potential to deliver high concentrations of therapy directly into tumors. In your experience, what are the logistical and clinical challenges of intratumoral delivery in lung cancer, and how does JNJ-1900 address them?

Traditionally, in the lung cancer world, we've discussed the difficulty of obtaining adequate tissue biopsies. Particularly in the context of lung cancer, especially non-squamous cancer, molecular characterization is incredibly important for guiding appropriate treatment. For a decade or two, there's been a long-standing conversation about how challenging it can be to get enough tissue.

JNJ-1900, however, represents the reverse of that. Instead of taking something out, you're putting something in. The logistical barriers are exactly the same: you have to make the procedure safe, feasible, and comfortable for the patient. What has changed isn't necessarily something specific to JNJ-1900, but rather the evolution of biopsy modalities. I'm particularly inspired by the development of interventional bronchoscopy methods.

The traditional biopsy is performed from the outside-in. With CT guidance, a needle is inserted through the skin, through the lining of the lung (called the pleura), and into an area of the tumor. This method carries a very real risk of pneumothorax, or, in simpler terms, a collapsed lung.

Bronchoscopy is the opposite approach. You go through the trachea (the breathing tube), down through the airways, and then move from the inside-out, progressing from the airways in the middle of the lung outwards toward a lymph node, primary tumor, or whatever the target may be. Modern bronchoscopy can reach quite far out, accessing most places in the lung. This is important because the patient is sedated for the procedure, leading to less discomfort during the process.

Crucially, the rate of pneumothorax or collapsed lung is quite a bit lower. In the hands of a skilled interventional bronchoscopist, you can reach almost anywhere in the lung pretty safely and comfortably to introduce the product.

Beyond safety, are there any early indications of efficacy or biological activity in the current JNJ-1900 study cohort that suggest potential for improving outcomes in patients with localized lung cancer?

The best indication we have for efficacy in the localized setting is the efficacy observed in the metastatic setting. My greatest fear when treating a patient with localized lung cancer with the goal of cure is that they will experience a recurrence with distant spread. Metastatic or distant spread is what causes most of the suffering and death in lung cancer. Therefore, novel therapeutics for lung cancer are primarily aimed at improving this distant control.

Historically, this has been achieved with systemic medications, which are effective because they can reach nearly every part of the body via the bloodstream. JNJ-1900, however, offers a very novel "have your cake and eat it too" strategy. You're performing a local intervention, but what's truly exciting for me isn't just that it helps effectively target the local tumor. It also contributes to distant control. When you treat one spot with JNJ-1900 and then introduce pembrolizumab, you achieve better control at distant sites.

This phenomenon, where treating one area leads to efficacy elsewhere, is called the abscopal effect. Historically, it was something radiation oncologists talked about a lot more than it actually occurred in the real world, probably at a ratio of at least 20 to one. However, there are now real abscopal effects observed in metastatic disease with JNJ-1900. This gives me a lot of hope that treatment in the localized context will significantly improve distant control.

Looking ahead, how do you envision the role of radioenhancers like JNJ-1900 evolving within standard lung cancer treatment regimens, particularly as part of multimodal strategies that aim to reduce systemic toxicity and improve long-term disease control?

This is a highly speculative question, but I'm happy to offer some thoughts, with the understanding that this is a very uncertain area. I'm personally very intrigued by recent data exploring why immunotherapy often fails when combined concurrently with radiation. Most famously, these failures are observed in head and neck cancer, another area of my interest. We have multiple trials showing that adding immunotherapy at the same time as radiation doesn't seem to help.

There's some data suggesting that this lack of benefit might be because the radiation is obliterating those first draining lymph nodes that are crucial for immune system activation. When you have cancer in a specific spot, that first draining lymph node is where the immune system initially encounters foreign elements — what we call antigen presentation — to which it might react.

Therefore, I'm generally intrigued by the idea of exciting approaches like JNJ-1900 being given neoadjuvantly. The concept is that before you obliterate those lymph nodes, you deliver a small burst of hypofractionated radiation, which is what you do with JNJ-1900. Coupled with its known immune-stimulating properties, this timing might combine very well and prove to be a clever and useful approach.

Transcript has been edited for clarity and conciseness.

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