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Despite the paradigm-changing impact of immunotherapy on cancer treatment, only a minority of patients obtain long-term benefits from the treatment. The most common estimate is that have durable responses. Certain types of tumors make up the majority of that 20%, such as melanoma, non-small cell lung cancer, and certain colorectal and kidney cancers. On the other hand, some tumors respond poorly to immunotherapy -- pancreatic cancer, brain cancer, and prostate cancer, to name a few.

Cancers that respond well to immunotherapy are often called "hot" tumors, whereas the poor responders are called "cold." First used to , the terms hot and cold referred to the type, density, and distribution of immune cells within the tumor microenvironment. But the terms hot and cold are far from black and white in the field of immuno-oncology.

"A hot tumor has a lot of immune cells in it, and a cold tumor does not, in general," said Drew Pardoll, MD, PhD, of Johns Hopkins University in Baltimore. "Hot tumors tend to have a greater number of lymphocytes, in particular T cells, certainly CD8 but probably also CD4, cells that are specific for various antigens in the tumor [and] that tends to correlate with tumor mutational burden and PD-L1 expression."

"But those correlations, while they sort of hold up in general, if you look at one tumor type versus another tumor type, are very rough and imperfect. There are many other factors that ultimately determine, beyond whether or not there are lymphocytes in the tumor, how many of them are tumor-specific and what are their qualities."

Cold tumors have become efficient at "creating a T-cell exclusionary bubble that protects the bulk of the tumor cells that you'd have to get rid of in order to regress the tumor," said Michael Curran, PhD, of the University of Texas MD Anderson Cancer Center in Houston. In simple terms, immune cells are "kind of locked out."

"It's not a one-step process," Curran continued. "[The barrier] consists of a stromal barrier or physical barrier at the outer edge, which has a lot to do with cancer-associated fibroblasts and deposition of an abnormally dense collagen matrix."

Properties that help define cold tumors include changes in the vasculature and endothelium, said Curran. T cells have to exit blood vessels to get into tumors, and many cold tumors have irregular vasculature that leads to a hypoxic environment that "is very inhospitable to T cells."

"When we look at [cold] tumors, what we're really seeing is the lack of accumulation of T cells, as opposed to lack of entry," he added.

Improved understanding about the properties of immunologically hot and cold tumors has given rise to numerous strategies to convert cold tumors to hot and to make immunogenically hot tumors even more responsive to immunotherapy.

"In my lab, we use a working model called the T-cell-inflamed tumor microenvironment," said Jason Luke, MD, of the University of Pittsburgh Medical Center. "The model has been used by a number of companies, with some success, with the fundamental underlying biology, meaning that the triggers that start the immune system are present in some tumors. The immune system is primed and ready to do something good if you give it an immunotherapy."

"Unfortunately, probably the majority of people with cancer, including breast, colon, and prostate cancer, functionally speaking, they never have that phenotype. Then checkpoint blockade essentially never works in those tumor types. That sort of concept, though, can be useful because you can start to think in a hypothesis-driven manner about what we could do that would actually trigger those immune responses."

Current approaches to triggering immune responses in tumors could fill numerous books. One popular strategy involves development of bi-specific T-cell-engaging antibodies. One component of the construct facilitates T cell entry into a tumor and the targeting arm confers specificity to the T cell.

"When T cells get activated, they don't just kill their target, but they also make cytokines, chemokines, secreted molecules that attract additional T cells to the area," said Pardoll. "When a T cell recognizes a pathogen, it basically sends out alarm signals to bring in more of its friends, essentially saying, 'Hey, here's where the problem is.' This is essentially what engineered bispecifics are doing."

Development of bispecific antibodies has been driven by advances in protein engineering, which in turn has been "revolutionized" by artificial intelligence to take fragments of natural proteins and modify them to enhance functionality toward a target.

"In many ways, protein engineers are the unsung heroes," said Pardoll. "They've been able to improve the half-life and extend it to do all kinds of things with what we sometimes call a tool compound, for proof of principle. Turn that into a drug candidate to bring to patients. I think we're beginning to see the early parts of an explosion in this area."

Along the same lines, engineered approaches have been brought to development of adoptive cell therapy to stimulate migration of T cells into tumors. Getting even a few cells inside a tumor "opens a crack in the door to bring in more T cells." Opportunities for engineered adoptive cell therapy are "phenomenal," said Pardoll.

Adoptive-cell transfer and bispecific antibodies also make Luke's short list of strategies that have potential to make an impact on cancer immunotherapy in the near future. CAR T-cell therapy has yet to duplicate its impact on hematologic malignancies in solid tumors, but "we're seeing some small signs that something good is starting to happen." The approval of tumor-infiltrating lymphocytes for melanoma was a "watershed event. That opens the gates."

Luke is collaborating with Immatics in the development of a T-cell receptor-transduced T-cell product that targets PRAME, an antigen expressed in melanoma. In preliminary clinical trials, 50% of patients with treatment-refractory melanoma have responded to the drug.

The promise of bispecific antibodies was evident in the recent FDA approval of tarlatamab (Imdelltra), a delta-like ligand 3 (DLL3)-targeted bispecific antibody. In a pivotal clinical trial of treatment-refractory small cell lung cancer, more than a third of patients achieved objective responses with the bispecific agent, with responses of 50% or higher .

"[Tarlatamab] is super interesting, because small cell lung cancer is one of the coldest tumors, and here's an immunotherapy that has a 50% response rate in refractory patients," said Luke.

Pancreatic cancers have perhaps the most daunting barrier to T-cell migration and activation. The microenvironment has the densest collagen and cancer-associated fibroblast network of almost all cancers, said Curran. Along with the rigid microenvironment, vascular constriction and hypoxia are among the highest found in tumors. Collectively, the characteristics create what has come to be called an immune "desert."

Secondary to the lack of T cells is a poor accumulation of dendritic cells, the antigen-presenting cells necessary to mobilize T cells, Curran continued. Finally, T-cell trafficking is very poor, as compared with tumors that are more responsive to immunotherapy. Still, clinical researchers have begun to find ways to extend benefits of immunotherapy to some patients with pancreatic cancer.

Surgery remains key to outcomes in pancreatic cancer, but only 20-25% of patients have resectable tumors at diagnosis, and almost all patients recur within a year or 2 after surgery, said Curran. A technique pioneered at Memorial Sloan Kettering Cancer Center in New York City has begun to improve the outlook.

Patients receive postoperative therapy that includes a neo-antigen vaccine in an attempt to get around the inadequate antigen awareness of pancreatic cancer. The vaccine induces responses to the antigens, and patients receive adjuvant treatment with a PD-(L)1 inhibitor and chemotherapy.

"What they found is that the patients who responded, in terms of making T cells to those antigens that were in the vaccine, had almost no relapses in the first 2 years," said Curran. "Among the patients who did not respond, only 20% or 30% of them had not recurred at 2 years."

Similar good news has come from studies of preoperative treatment with dual checkpoint inhibition -- CTLA-4 and PD-(L)1 -- in hepatocellular carcinoma, another immunologically cold tumor, though not to the extent of pancreatic cancer. About 20% of patients are surgical candidates at diagnosis and half of patients recur in the first 2 years. About 30% of patients had a major pathologic response, and none of those patients had cancer recurrence during the first 2 years of follow-up.

"Even if we haven't been able yet to tackle advanced disease in these cold tumors with immunotherapy, I am really encouraged by the amount of impact we can have in at least some patients who otherwise don't have a real curative-intent therapy," said Curran.

Antibody-drug conjugates (ADCs), combined with immunotherapy, also has generated some optimism in hard-to-treat cancers. Many of the clinical studies are still in the pilot stage, but early results are encouraging. Treating advanced bladder cancer upfront with a nectin-4 ADC and a PD-(L)1 inhibitor has led to "phenomenally better results than any of the prior therapeutic attempts." Similarly encouraging results have come from early studies of ADC-checkpoint inhibitor combinations in lung cancer.

"I think you're going to see some of these trickle down, and ADC combinations will emerge in colder settings, like colorectal cancer and breast cancer," said Curran.

In his own lab, researchers have developed a drug that inhibits both PD-L1 and PD-L2. Studies in mice have shown that the drug, called an immune checkpoint cytoreduction agent, depletes much of the barrier associated with immune exclusion. The drug's evaluation has reached clinical trials.

"We've seen two things that really excite us," said Curran. "Patients who have cold cancers that don't respond to PD-1 blockade have responded to this drug, and patients who have already failed a PD-1 inhibitor have also responded. So at least we know the drug is doing something different."

"What we hope is that, for the 55% of patients who have cold tumors that don't have an approved immune checkpoint indication, this drug will be able to expand the range of patients who are eligible to get these kinds of benefits from immunotherapy."

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