Breaching Cancer’s Defenses

Pancreatic ductal adenocarcinoma (PDAC) is unique among cancers for its survival mechanisms, which include the ability to survive with limited blood supply and low oxygen, and to protect itself from the immune system. The lack of angiogenesis means that it’s difficult for chemotherapy to reach the cancer cells; the hypoxic tumor environment means that radiation therapy is of limited use; and the ability of the cancer to induce inflammation and condition immune cells in its favor means that it’s able to avoid the body’s natural defenses. As a result, despite advances both in treatment options and in our understanding of the disease, we remain unable to effectively penetrate PDAC’s fortress – the majority of patients present with locally advanced or metastatic disease that is inoperable, meaning that they have only months to live, and no known therapy provides lasting benefit.

The immune advantage

In previous research, we were able to deplete a particular subset of immune suppressor cells in PDAC and unmask the ability of the adaptive immune response to target the cancer (1). Continuing on from this work, we decided to investigate a way of overcoming the immunological barriers set up by PDAC, knowing that developing an effective immune therapy to treat this disease was likely to change the therapeutic landscape, and that the principles we learned would likely translate to other types of solid tumors. T cell therapy is not entirely new – it’s currently under investigation in a variety of leukemias and lymphomas. But treating solid tumors with T cells is harder, because it’s not always possible for the cells to penetrate the tumor tissue. So we knew that if we were able to develop a method that allowed T cells to attack the PDAC effectively, we might be able to broaden our horizons to include other tumors as well.

Immunotherapy is quite attractive because it’s highly specific to targeting the malignant cells, leaving healthy tissue unharmed. T lymphocytes, the type of cell we engineer to target and kill cancer cells, have the ability to form memory – so their antitumor activity can be long-lived. Lastly, immunotherapy lets us take advantage of millennia of evolution. T lymphocytes naturally traffic throughout all of the body’s tissues. It’s conceivable that no site is off limits, including distant metastases, dormant tumor cells and desmoplastic tumors. This is particularly important in PDAC tumors because of their ability to form a dense shell around themselves, compressing blood vessels and preventing chemotherapy access.

An engineered attack

The main issue with the current treatments is that they have minimal, if any, clinical benefit. Chemotherapy is not specific, very toxic and typically has only transient or palliative benefit. It’s also unable to penetrate bulky pancreatic tumors due to high interstitial pressure and compressed blood vessels. And of the minor population of pancreatic cancer patients who are able to undergo surgery, only 20 percent will survive for five years – so even surgery isn’t curative in most patients. It’s clear that we need a better way to attack these tumors.

Our immunotherapy method involves isolating a population of T lymphocytes and engineering them to express a particular affinity-enhanced T cell receptor. This receptor specifically recognizes an epitope of a protein overexpressed by tumor cells. We chose to target the protein mesothelin, which is highly expressed in most PDACs, as well as in several other cancers. After our T cells are ready, we expand them in culture and transfer them back into patients – who, in this preliminary study (2), were mice.

Eight days after infusing our T cells into the mice, we observed increased tumor cell apoptosis, showing that the cells were doing their job. But by day 28, that effect had been lost, thanks to the inhospitable environment of the PDAC tumors. We provided the mice with a second infusion of the cells to see whether or not the tumors remained susceptible, and saw the same effects again. Eventually, we randomized mice to receive either our T cells or a control T cell infusion every two weeks – and saw that, while control mice showed consistently progressing disease, those receiving our treatment showed objective responses, including increased tumor cell apoptosis, decreased metastatic disease and malignant ascites, and almost double the median survival time (54 days in control vs. 96 days in treated mice).

Taking T cells to trial

In these preclinical studies, the engineered T cells preferentially accumulated in the tumor and metastases, killed cancer cells, persisted indefinitely, and prolonged survival. They showed another advantage as well – they specifically targeted the cancer without toxicity to the mice. Some of the proteins that we target are also expressed at low levels in some normal tissues, which means that there is potential for some toxicity, but after extensive evaluation in our preclinical models, we detected none. So not only are these T cells able to penetrate the biophysical barriers that chemotherapy can’t, they offer the chance for an improved safety profile as well.

But this is a living cell therapy, which means it’s more cumbersome to generate and requires access to an experienced good manufacturing practice (GMP) facility. And at the moment, the suppressive tumor microenvironment shuts down T cells over time – meaning that patients must receive regular infusions, increasing the burden on both patient and facility. We are currently working on how best to refine our approach so that we can sustain T cell expansion and function within the harsh tumor environment.

In the meantime, our first priority is to translate these result to patients as quickly as possible. We now have the equivalent T cell receptors for engineering human cells and hope to open a trial in the near future. My hope is that our approach will eventually significantly prolong survival in patients with advanced pancreatic cancer. The fact that it’s more technically challenging to deliver is less of a concern – if we have an effective solution, it will change how patients are treated and ultimately bypass the need for toxic chemotherapies altogether.

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