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New drug combinations are being tested on cancer tumors. Inuk Studio/Stocksy
  • Although there are treatments that facilitate the removal of cancer cells by the immune system, cancer patients often transiently respond to immunotherapies, such as immune checkpoint inhibitors, before developing resistance.
  • A recent study conducted in a mouse model of immunotherapy-resistant pancreatic cancer describes a novel therapeutic, PD1-IL2v, that caused tumor regression in animals.
  • Although PD1-IL2v only prevented tumor relapse in 40% of mice, combining PD1-IL2v with another clinically available immune checkpoint inhibitor prevented relapse in 90% of the mice.
  • These findings pave the way for the evaluation of this drug combination in clinical trials to assess its therapeutic potential in humans.

Researchers have previously used interleukin -2 (IL-2), a signaling protein, to stimulate a type of immune cell called cytotoxic or killer T cells to kill immunotherapy-resistant cancer cells.

However, high concentrations of IL-2 have been needed to produce the desired therapeutic effect, resulting in adverse effects.

A recent study published in the journal Immunity shows that a novel therapeutic, PD1-IL2v, consisting of an engineered form of IL2 fused to an antibody targeting the PD1 protein expressed on the surface of cytotoxic T cells can allow the use of lower concentration of IL-2 while causing tumor regression in a mouse model of immunotherapy-resistant pancreatic cancer.

In addition, researchers report that PD1-IL2v was particularly effective in preventing relapse when used in combination with the immune checkpoint inhibitor anti-PD-L1.

Dr. Santosh Kesari, a neurooncologist and director of neurooncology at Providence Saint John’s Health Center in California and chair of the Department of Translational Neurosciences and Neurotherapeutics at Saint John’s Cancer Institute, and regional medical director for the Research Clinical Institute of Providence Southern California, was optimistic about the findings.

“This new study highlights a potential way to overcome resistance to checkpoint immunotherapies that don’t help most solid tumors by locally activating immune cells in the tumor microenvironment with the delivery of an engineered cytokine called IL-2v,” he told Medical News Today. “This approach enables more immune cells to infiltrate the tumor and kill tumor cells and increase survival in an animal model.”

The central function of the immune system is to recognize and eliminate bacteria, viruses, and other potentially harmful substances.

The immune system performs these functions by identifying “non-self” proteins or molecules, known as antigens, expressed by pathogens and infected or damaged cells.

In addition, the immune system can also recognize antigens expressed by cancer cells and eliminate them. The growth of cancerous cells elicits an immune response involving a complex interaction between several types of immune cells.

This includes cytotoxic CD8 T cells, a subpopulation of white blood cells, that express the CD8 cell-surface protein. Upon their activation after exposure to an antigen, these CD8 T cells can help kill cancer cells.

Previous studies have found that the levels of cytotoxic CD8 T cells infiltrating the tumor can predict the clinical outcomes of cancer and responsiveness to immunotherapies.

However, cancer cells can evade this immune response by inducing changes in the tumor environment and suppressing the activity of CD8 T cells. Immune checkpoint proteins are molecules expressed on the surface of immune cells that help to regulate the immune response. These immune checkpoint proteins are activated upon binding a partner or complementary protein on other immune cells.

Activation of the immune checkpoint protein suppresses the immune response and prevents damage to healthy tissue. For instance, binding of the programmed cell death protein-1 (PD-1) immune checkpoint protein expressed by CD8 T cells to the complementary PD-1 ligand-1 protein (PD-L1) expressed on other immune cells inhibits the activity of CD8 T cells.

Cancer cells can also produce proteins, such as PD-L1, that bind to immune checkpoint proteins to inhibit the stimulation of CD8 T cells and other immune cells that can detect or eliminate cancer cells. To restore the activity of cytotoxic T cells against cancer cells, scientists have developed immune checkpoint inhibitors, which are therapeutics that block the binding of immune checkpoint proteins to their partner proteins.

Although immune checkpoint inhibitors are effective in causing tumor regression, a majority of cancer patients eventually develop resistance to these therapies or do not respond to the treatment. To overcome these shortcomings, clinicians have used the cytokine interleukin 2 (IL-2) to stimulate cytotoxic T cells to eliminate cancer cells.

However, treatment with IL-2 can also activate regulatory T cells, another type of T cell, that suppress the activity of cytotoxic CD8 T cells. Hence, researchers have developed an engineered variant of IL-2, known as IL2v, that can selectively stimulate cytotoxic T cells without activating regulatory T cells.

In addition, high doses of IL-2 are needed to reach the tumor and produce the desired therapeutic effects, resulting in adverse effects. To circumvent this obstacle, researchers have developed a form of IL-2v conjugated with an antibody against PD1 (anti-PD-1), known as PD1-IL2v. The PD1 molecule in this antibody-cytokine conjugate facilitates the targeting of T cells that have infiltrated the tumor tissue.

In the new study, the researchers examined the ability of anti-PD1-IL2v to induce the regression of tumors in a mouse model of pancreatic cancer. The mouse model used in the study shows resistance to immune checkpoint inhibitors and other immunotherapies.

The researchers reported that about 10% of the cells in the pancreatic tumor of untreated mice were CD8 T cells, with nearly 5% specifically targeting the pancreatic cancer cells.

Treatment with anti-PD1-IL2v resulted in a 10-fold increase in the infiltration of CD8 T cells targeting the pancreatic cancer cells in the tumor tissue.

Moreover, treatment with anti-PD-ILv2 produced a greater increase in CD8 T cells in the pancreatic tissue than either the anti-PD1 antibody or IL2v conjugated with a non-specific antibody alone or in combination.

Exposure to antigens results in the activation of naive T cells that are dormant. These naive CD8 T cells mature into effector CD8 T cells that can then eliminate infected or cancer cells.

Mice treated with anti-PD-1-IL2v showed increased activation and proliferation of CD8 T cells, resulting in an increase in effector CD8+ T cells that had previously encountered an antigen. Such effector T cells are characteristic of an immune response, such as one observed in response to an infection or to cancer cells.

In addition, the population of CD8 T cells in the pancreatic tissue also included cells with stem cell-like properties that were specific for the pancreatic tumor. These stem-like CD8 T cells can continually divide to produce tumor-specific effector CD8 T cells and new stem-like CD8 T cells. Thus, the presence of stem-like CD8 T cells can help produce a sustained anti-tumor response.

Cancer cells are able to evade the immune system by causing changes in the immediate tissue environment, including the blood vessels, to suppress the infiltration of immune cells.

In the current study, anti-PD1-IL2v treatment induced the formation of high endothelial venules, which are specialized blood vessels that can facilitate the migration of CD8 T cells into the tumor site. Notably, studies have found that the formation of high endothelial venules in tumors is associated with reduced tumor size.

The researchers reported that two to four weeks of anti-PD1-IL2v treatment led to tumor regression in all mice, but the tumor relapsed in 60% of the mice. The mice with relapsed tumors showed a decline in the number of tumor-specific CD8 T cells in the pancreatic tissue.

In addition, PD-L1, the ligand for PD-1, was upregulated after anti-PD-1-IL2v treatment, with a further increase in PD-L1 expression in relapsed tumors. This increase in PD-L1 was prominent in the tumor blood vessels and macrophages, another type of immune cell, in relapsed tumors.

Given the increase in the expression of PD-L1 in relapsed tumors, the researchers examined whether the use of PD1-IL2v in combination with anti-PD-L1 antibodies could lead to higher rates of tumor regression.

The researchers said anti-PD1-IL2v combined with anti-PD-L1 led to tumor regression in the absence of relapse in 90% of treated mice, whereas anti-PD-L1 did not produce any beneficial effects. Moreover, as previously noted, only 40% of the mice treated with anti-PD1-IL2v showed complete tumor regression.

The researchers then examined the mechanisms that may explain the higher efficacy of the anti-PD1-IL2v combined with anti-PD-L1 antibodies.

PD1-IL2v, regardless of its use alone or in combination with anti-PD-L1, resulted in the greater infiltration of effector CD8 T cells in the pancreatic tissue than anti-PD-L1 alone.

Moreover, the increased population of CD8 T cells consisted of effector memory T cells that have a longer life than normal effector CD8 T cells and can more rapidly respond to tumor cells.

T cells express T-cell receptors (TCR) on their surface that identify and bind to specific short fragments of antigens presented by other immune cells.

In the study, the use of anti-PD1-IL2v increased the number of CD8 T cells with TCRs specific for the tumor cells, and the population of these CD8 T cells further expanded upon combining PD1-IL2v with anti-PD-L1 antibodies.

The researchers said that treatment with anti-PD-L1 in isolation had a more profound effect on the blood vessels and macrophages in the tumor tissue than on CD8 T cells. The ability of cancer cells to evade elimination by CD8 T cells has been attributed to the infiltration of the tumor tissue by macrophages.

Macrophages can engulf cancer cells and can activate other immune cells, including CD8 T cells, by presenting fragments of engulfed tumor cells. However, macrophages in tumor tissue can also assume a different form that promotes tumor growth. These macrophages can secrete signaling proteins called cytokines that prevent the recruitment and suppress the activity of T cells while promoting tumor growth.

In the present study, macrophages from tumors of untreated mice showed greater expression of genes associated with suppressing an immune response. In contrast, treatment with anti-PD-L1 resulted in the greater expression of pro-inflammatory cytokines and other genes associated with stimulating an immune response. Moreover, macrophages from tumors of untreated mice suppressed the proliferation of T cells to a greater extent than those from anti-PD-L1 treated mice.

Endothelial cells that form the inner lining of blood vessels play a critical role in the infiltration of white blood cells during an inflammatory response.

In the study, the researchers found that the endothelial cells from the tumors of mice treated with anti-PD-L1 also showed a greater pro-inflammatory response that may facilitate the recruitment of CD8 T cells.

Summarizing these results, Dr. Douglas Hanahan, a study author and an oncology researcher at the Swiss Federal Institute of Technology Lausanne (EPFL), said, “PD1-IL2v induces stronger and more specific expansion of anti-tumor T cells compared to conventional anti-PD-1 therapy by stimulating a specific subtype of T cells, whereas anti-PD-L1 targets and disrupts barriers erected in the tumor microenvironment, namely pro-tumoral macrophages and tumor vasculature, which collaborate to counteract the anti-tumor immunity.”

“This combination led to improved survival in mouse cancer models initially resistant to immunotherapies. These provocative results present a rationale for clinical trials aimed at evaluating the combination therapy of PD1-IL2v and anti-PD-L1, especially in immunotherapy-resistant cancer patients. Our collaborators at Roche have launched a clinical trial of PD1-IL2v with and without anti-PD-L1 in solid tumors (NCT04303858); we are looking forward to the first clinical results of this new therapeutic modality,” he added.