The immune system has evolved to protect the body from potential threats, including bacterial diseases such as plague, cholera, diphtheria, and Lyme disease, and viral pathogens, including influenza, Ebola virus, and SARS CoV-2.

But the complex immune system defense network struggles when the body’s own native cells turn rogue, leading to cancer. While the immune system may engage to try to rid the body of malignant cells, its efforts are frequently thwarted as the disease progresses unchecked.

A team led by Grant McFadden, PhD, and Masmudur Rahman, PhD, at the Biodesign Center for Immunotherapy Vaccines and Virotherapy, at Arizona State University, proposed a new line of attack that shows promise for treatment-resistant cancers. Their approach combines oncolytic virotherapy, a technique using cancer-fighting viruses, with existing immunotherapy techniques, to boost the immune system’s capacity to target and destroy cancer cells.

The researchers reported on their studies in Cancer Cell, in a paper titled, “Induction of tumor cell autosis by myxoma virus-infected CAR-T and TCR-T cells to overcome primary and acquired resistance.”

The immune system is composed of a range of specialized cells designed to patrol the body and respond to threats. It’s a continual battle against pathogens, which evolve sophisticated techniques to attempt to outwit immune defenses, propagate in the body, and cause disease. Cancer presents a unique challenge to the immune system, as tumor cells often lack the identifying cell features that allow the immune system to attack them by distinguishing self from non-self.

Cancer cells can further short-circuit immune efforts to hunt and destroy them, through a range of evasive strategies. Researchers have been devising new adoptive cell therapy (ACT) strategies that are designed to help the immune system overcome cancer’s tactics of disguise. ACT technology often involves removing cancer-fighting T-cells, modifying their seek-and-destroy capacities, and reinjecting them into patients. Two forms of ACT immunotherapy, CAR-T cell therapy and T Cell Receptor Engineering (TCR), are both based on the same concept of treating cancer with activated T lymphocytes extracted from the patient.

The development of such therapies has been nothing short of revolutionary, and some cancer patients facing grim prospects have made remarkable recoveries following the use of immunotherapy. However, CAR-T and TCR therapies do have their limitations, and are often ineffective against advanced solid tumors. In such cases, cancer cells often manage to evade destruction by T cells by downregulating or losing the surface antigens, or MHC proteins, that T cells use to identify them.

Grant McFadden, PhD, directs the Biodesign Center for Immunotherapy, Vaccines, and Virotherapy. He is also a center director and professor at the School of Life Sciences. [The Biodesign Institute at Arizona State University]

As the authors noted, “Adoptively transferred T cells engineered to express chimeric antigen receptors (CARs) have shown some success in eliminating hematopoietic cancers, but have so far been limited in their efficacy against solid tumors, which account for most cancer deaths … Lack of a primary response (initial tumor regression) is most likely multifactorial and includes limited homing to and penetration of tumors, T-cell exhaustion, limited persistence, and an immunosuppressive tumor microenvironment.”

The new study shows how coupling immunotherapy with virotherapy may be an effective approach to addressing cancer resistance. Oncolytic viruses represent an exciting avenue of cancer therapy. Such viruses have the remarkable ability to target and kill cancer cells while leaving healthy cells unharmed, as well as enhancing the immune system’s ability to recognize and terminate cancer cells. However, as the authors explained, the strategy is not without challenges. “Oncolytic virotherapy is an emerging therapeutic modality for the treatment of cancer, but unfortunately, systemic delivery of oncolytic viruses using standard intravenous infusion has so far not achieved sufficient enrichment of viruses in metastatic tumor beds.

For their newly reported studies, the authors focused on the myxoma virus (MYXV), and specifically on using myxoma-equipped T cells. MYXV is a DNA virus that has a highly restricted host range and is only pathogenic to European rabbits,” the team noted. “MYXV is a promising and safe oncolytic virus because it selectively infects and kills a wide variety of tumor cells while sparing normal cells and tissues.”

For their research, the team tested myxoma virus-infected tumor-specific T (TMYXV) cells expressing CAR or TCR, which systemically deliver MYXV into solid tumors to overcome primary resistance. “… we investigated the potential to exploit CAR-T and TCR-T cells as MYXV delivery carrier cells by pre-infecting the T cells with MYXV ex vivo by a spin infection protocol (CAR-TMYXV and TCR-TMYXV).

Masmudur Rahman is a researcher in the Biodesign Center for Immunotherapy, Vaccines and Virotherapy. [The Biodesign Institute at Arizona State University]

The myxoma virus can target and kill cancer cells directly, but more usefully can induce an unusual form of T-cell directed cell death known as autosis. This form of cell death augments two other forms of programmed cancer cell death induced by T cells, known as apoptosis and pyroptosis. The team explained that through their research they observed “a special type of tumor cell death induced by CAR-TMYXV that has not been attributed to any T cell killing mechanism before but may contribute to the exciting observed antitumor potency … differing from classic apoptosis and pyroptosis induced by T cells, this special type of cell death, called autosis, can also mediate a potent type of bystander killing for antigen-negative tumor cells.”

During myxoma-mediated autosis, cancerous cells in the vicinity of those targeted by the therapy are also destroyed in a process known as bystander killing. This effect can considerably enhance the dual therapy’s aggressive eradication of cancer cells, even in notoriously hard-to-treat solid tumors.

A combined myxoma-immunotherapy approach could thus potentially be used to turn so-called “cold tumors,” which fly under the immune system’s radar, into “hot tumors” that immune cells can identify and destroy, allowing CAR-T cells or TCR cells to enter the tumor environment, proliferate, and activate.

“We uncover an unexpected synergy between T cells and MYXV to bolster solid tumor cell autosis that reinforces tumor clearance,” the team noted. “ … our data suggest the existence of a tumor cell autosis-triggering strategy dependent on MYXV and antigen-programmed CAR-T cells that strategically incorporates MYXV and tumor-specific T cells to overcome therapeutic resistance in solid tumors.”

Rahman further stated, “We are at the edge of discovering newer aspects of the myxoma virus and oncolytic virotherapy. In addition, these findings open the door for testing cancer-killing viruses with other cell-based cancer immunotherapies that can be used in cancer patients.”

The ability to radically reengineer oncolytic viruses like myxoma to target a range of resistant cancers provides a new frontier for the treatment of this devastating disease.