Strides in Cancer Treatment

A new paper shows that CART therapies can be unleashed against solid tumors.

We are finally in the payoff period in the decades-long war on cancer. Slowly, painfully, precision approaches are being developed to treat specific molecular lesions in ways that are superior to the old blunderbuss kill-everything approaches. At first, these treatments had only marginal effects, at astounding costs. But increasingly, the effects are lengthening and cures are in sight in some forms of cancer. One unexpected area of revolutionary progress has been immunotherapies, which in various ways help our immune systems attack cancers. It turns out that many cancers have tricks to hide from the immune system, and once those tricky dampening molecules are circumvented, dramatic reductions are possible. One paper recently described an anticancer vaccine made up of a witch's brew of targeting molecules, cancer antigens, and adjuvants, that achieves strong anti-melanoma action.

Another one of these immunotherapies is CART, or chimeric antigen receptor T-cell therapy. T cells have a receptor repertoire, just as B-cells do, which target things to be attacked- foreign pathogens, diseased states, etc. at molecules called antigens. One problem in cancer is that the cells are, originally at least, our own, so they mostly evade immune detection by having few "foreign" antigens. But there are nevertheless some antigens, comprised of normal molecules that are out of place (such as DNA found outside the cell) and "neoantigens" that are proteins expressed from the mutations in cancer cells. Additionally, as mentioned above, cancer cells express additional molecules (PD-L1) that can dampen even the immune response that does get generated by these few cancer antigens. So, the chimeric part of CART is taking the patient's own T-cells and engineering some of them to express new anti-antigen receptors that are relevant to the patient's cancer. Perhaps there is a mutant fusion protein that the cancer depends on. Perhaps the cancer displays an unusual surface molecule. Perhaps the tables need to be turned and PD-L1 targeted. There are many possible targets. 

CART therapies have, to date, been mostly directed at blood tumors. Solid tumors have extra protection in their micro-environments, and have not been good targets, though they necessarily have blood supplies and thus exposure to systemic T-cells. A recent paper blows open this field by revealing a magic molecule that plays a very significant role in the structure of solid tumors- the urokinase receptor. The urokinase plasminogen activator receptor (uPAR) is heavily expressed on senescent cells and many solid tumors, but rarely expressed elsewhere. Indeed, its expression correlates with tumor aggressiveness. Plasminogen is a protease that is sort of a cleanup crew for the circulatory system and body generally. It breaks up blood clots, and digests follicle tissues allowing ovulation. It encourages wound healing and discourages fibrosis- the buildup of scar tissue. However, in the cancer setting, the same activity seems to encourage fibrosis in a sort of constant wound healing state. Reviews in this field are rather confused about the direction of action. But one thing is clear- uPAR has myriad signaling activities relevant to tissue repair and immune activation that are not all dependent on the uPA (plasminogen activator) and plasmin activation system. Indeed, it is expressed not just in cancers, but in many other fibrotic settings.

A wide array of proteins are assessed here for their expression in a cancer tissue sample. uPAR is in red at the upper left. The matrix on the right shows the correlation of expression in a wide variety of cell types and tissues, like cancer-associated fibroblasts (CAFs), monocytes/macrophages (Mo/Mac), and with the protein fibroblast activation protein alpha (FAP).

The authors sought to target CART cells against uPAR, principally as a targeting device, since this marks many solid tumors and correlates with metastasis and rapid cancer progression, in addition to inflammation and fibrosis. While only tested in mice, the results were remarkable. 

"CAR T cells targeting the D2-D3 domain of uPAR display broad antitumor activity in xenograft, syngeneic, and patient-derived models, including in adjuvant and combination settings, supporting the concept that targeting conserved malignant cell states can enable therapeutic strategies that transcend tumor type. ... our prior work shows that uPAR CAR T cells targeting senescent cells remodel fibrotic tissues, and, as shown herein, this remodeling is associated with CAR T cell infiltration and cytotoxic activity. Similarly, parallel work demonstrates that uPAR CAR T cells exhibit potent efficacy in glioblastoma models and can co-target supportive stromal cells."

This is to say that these CART cells target not only tumor cells, but the surrounding solid tissues (stromal cells) that they rely on. That is the key to defeating solid tumors. It also indicates that other autoimmune and fibrotic conditions may be addressable with this therapy as well. 

Treatment effects from the CART therapy in mice, against several tumors. The red graphs are controls, and the blue graphs are treatments. Top is the tumor volume over time, while at bottom is survival of the mice over time.  Lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), high-grade serous ovarian carcinoma (HGSOC), and pancreatic ductal adenocarcinoma (PDAC).

The results of treatment of xenografted human ovarian tumors into susceptible mice, at 3 weeks, bottom. On the left is the control, while the other two sets were treated with CART cells against uPAR.

The authors note that relapses were seen occasionally, but that in these cases, the uPAR target was still highly expressed. That suggests firstly that it is difficult for tumors of these targeted types to do without uPAR, and secondly that something else went wrong with the tailored CART therapy, other than that its target went away. Perhaps future work can enhance its penetration or activity. The researchers also strained to make their model systems as human-relevant as possible, using cancer tissue transplanted (xenografted) from human cell lines, human CART cells, and mice with transplanted immune systems from humans. This work is thus not only a scientific breakthrough of the highest order, but is a technical tour de force as well. It also ends up with a variety of patent declarations and commercial ties, indicating that this breakthrough is being fully milked by its inventors and commercialized at breakneck speed.

One major problem with this mode of therapy is that CART cells require a great deal of engineering. First, antibodies against uPAR were developed in mice or other species. Then the genes from those immune systems were recovered from those mice, to get the precisely recombined gene that expressed the antibody with highest binding activity against uPAR. Then that gene, hooked up to new transmembrane and intracellular domains, (specially selected to activate the T cell they will be put into), was introduced into a transformation vector and put into the T cells collected from the diseased mice. In humans, this treatment routinely runs a half a million dollars. It is incredibly ornate, and one expects that gene therapy will someday allow the patient's T cells to be directly modified in the body, without all the collection and laboratory work, (which takes months), given a high-quality gene encoding the antibody fragment that is generally applicable- not tailored to a specific patient.

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