Expert Point of View: Dan L. Longo, MD

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The term “abscopal” is from Greek roots that mean “away from the target.” Coined by R.H. Mole in 1953, it was used to label observed effects of radiation at a distance from the volume irradiated. Mounting evidence suggests an immunologic basis for the effect, but it should also be remembered that blood-borne products of the tumor may be involved, given that some metastatic tumors (eg, renal cell cancer and neuroblastoma) can, rarely, regress with surgical resection of the primary tumor.

Tumor-induced Immunosuppression

Tumors have a diverse repertoire of tricks to elude detection and attack from the immune system. As cancers, in general, originate from one’s normal cells, they typically have few recognizable differences from self. They can stop expression of HLA molecules, making T cells blind to their presence. They can impair antigen presentation. They produce factors that can kill immune cells or paralyze immune responses. They also use the immune system’s safeguards against autodestruction to protect themselves by inducing the expansion of regulatory cell populations (myeloid cells, monocytes, T cells, B cells) that inhibit the immune response.

As these factors (and others) contributing to tumor-induced immunosuppression have been elucidated, new interventions to overcome them are being brought to the clinic with impressive levels of success, including the mediation of abscopal effects. Antibodies to undo the tamping down of immune responses (eg, CTLA4, PD1) are showing meaningful response rates. Novel vaccine approaches are eliciting antitumor immunity. Immune stimulation (CD40 and OX40 activation) is making progress. And the strategy of arming and souping up T cells to kill tumors in adoptive transfer is joining graft-vs-tumor effects as an effective cell-based cancer treatment.

The Tasmanian Devil Mystery

So why are Tasmanian devils being extinguished by a tumor they are passing to each other?

Frankly, it is a surprise. Experiments conducted in the 1950s and 1960s on prisoners and chronically ill patients (tragically, without what we would consider informed consent) demonstrated that subcutaneous injection of live tumor cells from another person would not survive even in people with some immune compromise.

Based on theories about the evolution of the immune system, the first mediator of cell-based immunity (the amebocyte of the sponge) arose to fight off another member of the same species competing for space on the same rock. A very large percentage of an animal’s or a person’s T cells are potently alloreactive—that is, they respond to and kill cells from another member of the same species. Yet xenogeneic responses (those against another species) are relatively weak. The rejection of a tumor from another member of one’s species is usually major histocompatibility complex (MHC)-based (involving either major or minor antigens or both) and similar to the rejection of mismatched organs.

The canine transmissible venereal tumor follows the predictions of the fate of an allogeneic tumor, namely to be ultimately rejected by the host. Why are Tasmanian devils dying before they can develop an effective immune response against their tumor? Unfortunately, we do not know enough about the devil immune system to draw a conclusion.

Ongoing Work

Much interesting work is ongoing to sort out this mystery. Apparently only 20% of one population of devils (West Pencil Pine near Cradle Mountain) have developed the tumor, down from the 80% or more incidence among devils in the wild. Is the tumor changing or are the devils developing immunity? A decrease in the virulence of the tumor would be a welcome accompaniment to the gradual increase in scientific understanding that can combat this tragic disease.

Thankfully, the killing of a tumor that originated in another person is not a major problem in humans. However, overcoming a cancer’s successful adaptation to life in a syngeneic host is becoming an achievable goal. ■

Disclosure: Dr. Longo is deputy editor of the New England Journal of Medicine.

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