After years on the margins, intratumoral immunotherapy is drawing renewed attention following the FDA’s recent approval of vusolimogene oderparepvec (Tudriqev, Replimune), the second immunotherapy approved for intratumoral use.

The drug is approved in combination with nivolumab to treat advanced melanoma that has progressed after an anti-PD-1-containing regimen.

It wasn’t smooth sailing, though. The approval followed two rejections from the FDA — one in July 2025 and one in April 2026 — over insufficient evidence of effectiveness from the single-arm IGNYTE trial.

At a July advisory meeting, FDA panelists ultimately voted 10-3 that the IGNYTE results demonstrated the combination therapy’s clinical efficacy. But the panel debated the primary endpoint: The company reported an objective response rate of 33.6%, while the FDA figures were lower, with the FDA approval settling on 24.2%. The panel also noted that the trial could not establish how much of the response came from the injected drug vs nivolumab. Because the approval was based on surrogate measures, continued approval may depend on whether confirmatory trials verify clinical benefit.

The panel discussion reflects broader questions facing intratumoral immunotherapy: Can injecting a tumor trigger an immune response that improves outcomes beyond the injected lesion, and can this approach meaningfully improve patient outcomes?

Intratumoral immunotherapy is “a great idea,” but decades of testing indicate “it doesn’t seem to work that easily,” said advisory panelist Paul B. Chapman, MD, chief medical research officer at Weill Cornell Medicine in New York City, who voted against approval.

Bishal Gyawali, MD, PhD, medical oncologist and professor at Queen’s University in Kingston, Ontario, Canada, similarly noted that “there has not been convincing phase 3 data yet to say that these treatments improve patient outcomes.”

However, others remain enthusiastic about the approach. Hussein Tawbi, MD, PhD, professor at UT MD Anderson Cancer Center in Houston, who voted in favor of approval, characterized the approach as a “holy grail.”

So what does the evidence show, and can renewed interest translate into meaningful advances?

The Rationale and the Evidence

There is a biological rationale for intratumoral immunotherapy.

Delivering therapy directly into a tumor can achieve higher local drug concentrations while limiting systemic exposure. Intratumoral approaches are also designed to stimulate an immune response within the tumor. The broader aim is to generate a systemic T-cell response that can recognize and attack tumor cells at sites that have not been directly injected, including tumors that may otherwise be less immunologically active.

Just seeing some shrinkage in the target lesion alone is not convincing evidence that injecting the lesion worked, Gyawali explained. “If the treatment is really effective, we should see shrinkage of tumor elsewhere as well,” he said.

But whether such a cascade effect is the result of intratumoral immunotherapy or a systemic treatment remains an open question.

Response assessment poses other challenges. Immunotherapy can cause pseudoprogression, in which tumors temporarily grow before shrinking. Because intratumoral therapy is injected into some tumors but not others, researchers must determine how best to evaluate responses in uninjected lesions.

Although the idea of injecting tumors with drugs that can spur the immune system dates back decades, clinical progress has been slow. The first FDA-approved intratumoral immunotherapy, T-VEC (talimogene laherparepvec), was approved in 2015.

T-VEC, a herpes simplex virus type 1-derived oncolytic immunotherapy, was approved after a randomized phase 3 trial demonstrated a significantly higher overall response rate than with subcutaneous granulocyte macrophage colony-stimulating factor in patients with unresected stage IIIB to IV melanoma (26.4% vs 5.7%), with numerically longer overall survival (23.3 months vs 18.9 months; P = .051).

Intratumoral immunotherapy has become an active area of study. A 2024 review identified at least 175 active or planned intratumoral immunotherapy clinical trials in a variety of cancers outside of melanoma. The approaches under investigation vary widely, including oncolytic viruses, vaccines, immune checkpoint modulators, and other agents designed to stimulate antitumor immune responses.

But “the wind kind of went out of the sails with some pretty high-profile negative phase 3 studies,” said Rahul Sheth, MD, lead author of the 2024 review and associate professor at UT MD Anderson Cancer Center.

One example was the phase 3 MASTERKEY-265 trial of T-VEC plus pembrolizumab in patients with stage IIIB-IVM1c unresectable melanoma. Although an earlier phase 1b study of 21 patients reported a 62% objective response rate, the subsequent randomized trial of 692 patients found no significant improvement in progression-free or overall survival compared with pembrolizumab alone.

However, there have been some bright spots. A 2025 phase 3 randomized trial in patients with stage III melanoma found that, compared with upfront surgery, neoadjuvant intratumoral immunotherapy daromun improved recurrence-free survival (16.7 vs 6.8 months) and reduced the risk for distant recurrence by 40%.

Still, the evidence has largely come from early-phase proof-of-concept or safety trials, and randomized clinical evidence has remained “underwhelming,” said medical oncologist Jason Luke, MD, chief medical officer at Strand Therapeutics, a Boston biotech.

For instance, a phase 1/2 single-arm trial of 49 patients with recurrent glioblastoma found that intratumoral delivery of the oncolytic virus DNX-2401 followed by pembrolizumab did not meet its primary efficacy endpoint: The objective response rate was 10.4%, which was not significantly higher than the prespecified 5% benchmark. However, 12-month overall survival was 52.7%, exceeding a prespecified historical benchmark of 20%, and three patients who had durable responses remained alive at 45-60 months.

In another early signal, a phase 1 trial of SYNC-T, an in situ personalized immunotherapy, reported an 87% objective response rate, including complete responses in 53% of 15 patients with metastatic castration-resistant prostate cancer. The results are preliminary, however, and require confirmation in larger studies.

Working Out the Kinks

Outside of melanoma, promising signals have not yet translated into consistent success across the field, leaving trial design and practical delivery as important unresolved issues.

In June 2026, Aurélien Marabelle, MD, PhD, and his team at Gustave Roussy Cancer Center in Villejuif, France, hosted the first international symposium on intratumoral immunotherapy, bringing together about 100 experts from around the world. The meeting also attracted industry support. The organizers listed Johnson & Johnson, Boston Scientific, and GE HealthCare, among other companies, as supporters of the symposium.

Despite negative trials that have dampened industry interest, “there’s energy from all aspects, from industry, from big pharma side, small biotech, imaging companies,” said Sheth, who was on the symposium’s organizing committee. “That’s been a huge boon for us.”

Still, much of the symposium focused on practical challenges, including standardizing how treatment effects are measured as well as optimal drug delivery and imaging guidance.

In 2020, experts proposed iRECIST, an adaptation of standard response criteria designed to address some of these challenges. In 2024, the Society for Immunotherapy of Cancer recommended it as an exploratory tool in intratumoral therapy trials. But consensus on how best to assess responses in uninjected lesions remains elusive.

Despite the field’s ups and downs, “we believe there is opportunity to really impact people’s lives,” said Jorge A. Garcia, MD, chief of the Division of Solid Tumor Oncology at University Hospitals Seidman Cancer Center in Cleveland.

Disclosure information for the experts cited in the article was not available at the time of publication.