Cancer Vaccine Shows Potential against iNHL in Early Results

A new cancer vaccine still in clinical testing showed potential for driving disease remission in patients with advanced indolent non-Hodgkin’s lymphoma (iNHL) and may help restore efficacy of immunotherapies, including checkpoint blockade therapies.

The vaccine, administered directly to tumor lesions, was able to control or even shrink lymphoma throughout the bodies of some patients, boosting their anti-tumor immune responses, according to results from an ongoing trial.

Combining this vaccine with PD-1 checkpoint blockade may strengthen and extend treatment efficacy to more patients, even though this requires investigation in trials.

The study with the findings, “Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination,” was published in the journal Nature Medicine.

Standard therapy typically fails with this type of slow-growing, or indolent non-Hodgkin’s lymphoma, which is often resistant to immunotherapy with checkpoint blockade.

“Checkpoint blockade has had tremendous impact on cancer therapy, but only a subset of patients responds, and the response rate in iNHL is especially low,” investigators stated.

For reasons that are unclear thus far, CD8 T cells, or cytotoxic T cells, which are the basis of checkpoint blockade and other immunotherapies, are unable to recognize and kill iNHL.

For these cells to work, they first need to be primed. This happens when CD8 T cells bind short, tumor-specific protein fragments, referred to as tumor antigens, which work as “baits” that tell T cells which cells they need to target.

In theory, B-cell lymphomas could directly prime T cells, but researchers have now found this is not completely true. There is only enough priming to attack the tumor if CD8 T cells bind to tumor antigens displayed at the surface of other immune cells, called dendritic cells, through a process known as antigen cross-presentation.

Recognizing this need, researchers came up with a potential solution — a cancer vaccine designed to boost cross-presentation of dendritic cells and priming of T cells.

This vaccine is made of three components: Fms-like tyrosine kinase 3 ligand (Flt3L) to attract dendritic cells to the tumor site; low-dose, local radiotherapy to release tumor antigens; and a TLR3 stimulant (poly-ICLC) to activate dendritic cells.

Encouraged by earlier results, researchers started an early Phase 1/2 trial (NCT01976585) and tested their vaccine in 11 patients with advanced B-cell iNHL.

Participants were given nine daily injections of Flt3L into a single target lesion, then two doses of radiotherapy to the same lesion and eight intratumoral injections of pICLC.

Of the 11 patients who received the experimental vaccine, eight had partial or complete regression of the treated tumor.

Examination of the remaining tumors (not directly treated) that were spread throughout patients’ bodies showed that six patients developed stable disease or small reductions, two had a partial remission, and one had a complete remission, lasting three to 18 months.

Analysis of immune cells before and after vaccination revealed this approach was able to stimulate the infiltration of cross-presenting dendritic cells into the treated tumor, markedly improving priming of CD8 T cells that were able to recognize and kill tumors elsewhere in the body.

An important observation was that non-responding patients developed a population of PD-1-expressing T cells following vaccination, suggesting that combining the vaccine with PD1 blockade therapy would provide superior responses.

In fact, when researchers tried the vaccine in mouse models of iNHL, they saw that anti-PD-1 treatment alone was ineffective, but combined with the vaccine led to bulky cancer remission in 75% of the mice.

A boost in anti-tumor immune response was also reproduced in mice, where the vaccine stimulated recruitment of antigen-loaded and activated dendritic cells and promoted expansion of anti-tumor CD8 T cells.

This study was the first to show body-wide cancer remissions using this type of vaccine approach.

“This is especially remarkable given the bulky, advanced stage B-cell tumors that continued regressing for months after therapy, with concurrent sparing of healthy B cells,” researchers said.

They added, “Our results have broad clinical implications. Of the ~1,500 combination immunotherapies currently being assessed in clinical trials, more than 300 combine PD1 and CTLA4 blockade, an approach with promising efficacy but increased toxicity, indicating that additional checkpoint rescue of tumor-specific [T cells] can yield only incremental benefit.”