Promising experimental treatment makes cancer vanish in patients

By Stephen Beech

Cancer drugs that have been around for two decades were able to eliminate aggressive tumors in a "remarkable" clinical trial.

Two patients - one with the deadliest form of skin cancer called melanoma and another with breast cancer - saw their tumors disappear completely.

American scientists showed that an engineered antibody improved the class of drugs that had struggled to make good on their early promise.

The drugs - called CD40 agonist antibodies - had initially shown great potential.

But, while effective at activating the immune system to kill cancer cells in animal models, the drugs had only "limited" impact on patients in clinical trials.

They also triggered dangerously systemic inflammatory responses, low platelet counts, and liver toxicity, among other adverse reactions- even at a low dose.

But in 2018, researchers at Rockefeller University in New York engineered an enhanced CD40 agonist antibody so that it improved its efficiency 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 conduct a clinical trial to see the drug’s impact on cancer patients.

The results from the phase 1 clinical trial of the drug, dubbed 2141-V11, showed that six out of 12 cancer patients saw their tumors shrink, including two that saw them disappear completely.

Study first author Dr. Juan Osorio said: “Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable.

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

Professor Jeffrey Ravetch said: “This effect - where you inject locally but see a systemic response - that’s not something seen very often in any clinical treatment.

“It’s another very dramatic and unexpected result from our trial.”

He explained that 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 anti-tumor immunity and developing tumor-specific T cell responses.

In 2018, Prof Ravetch’s lab 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 anti-tumor immune response.

The research team 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.

They instead injected the drug directly into tumors.

Ravetch said: “When we did that, we saw only mild toxicity."

The findings became the basis of the clinical trial which aimed to determine a starting clinical dose of the drug and better understand the mechanisms underlying its effectiveness.

The trial included 12 patients who had various types of 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.

Ravetch said: “The melanoma patient had dozens of metastatic tumors on her leg and foot, and we injected just one tumor up on her thigh. “

"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.

Dr. Osorio said: “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.

“The drug creates an immune micro-environment within the tumor, and essentially replaces the tumor with these tertiary lymphoid structures.”

He says the presence of tertiary lymphoid structures (TLS) is associated with improved prognosis and response to immunotherapy.

The team also found TLS in the tumors they didn’t inject.

Dr. Osorio said: “Once the immune system identifies the cancer cells, immune cells migrate to the non-injected tumour sites."

The findings, published in the journal Cancer Cell, sparked several other clinical trials that the Ravetch lab is currently working on with researchers at Memorial Sloan Kettering and Duke University.

The trials are investigating 2141-V11’s effect on specific cancers, including bladder cancer, prostate cancer, and glioblastoma - all aggressive and hard to treat.

Nearly 200 people are enrolled in the various studies that the researchers hope will explain why some patients respond to 2141-V11 and others do not - and how to potentially change that.

Dr. Osorio said 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. “

He added, "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."