Most of the attention in the media is now focused on the several forms of cancer treatment grouped under the flattering term “Precision Medicine.” I find that the term raises my skepticism index just a bit; it’s like eating establishments labeling themselves “Gourmet Restaurants,” the implication being that joints not so identified are just feeding troughs for the undiscerning masses. What is medicine that is not included in the category “Precision Medicine?” Do we call it “Slapdash Medicine?”
However, subduing my skepticism for the moment, let me concede that the term has some meaning besides the preening. Cancer has typically been classified as to its location – breast, lung, liver, prostate, and so on. This classification carries with it an implicit assumption that all the cancers within each of those classifications more or less resemble one another, and can more or less be treated in the same way. This is where precision medicine is genuinely different. There are many different types of breast cancer, and their treatment, and, perhaps most important, their prognoses, can be very different. The goal of precision medicine is exactly that – to distinguish between the types of cancer, and between individual cancers, and to treat each cancer in the most effective way available.
Before going down that pathway, let me first review a bit about what makes cancer be cancerous. Cancer cells that emerge in different parts of the body do not much resemble one another. They are mutations of entirely different cells. In some cases, the mutations are random errors of transcription of the genetic material. Most of these will simply die off, but in some cases the mutations include features that not only enable the mutated cells to survive, but confer characteristics that make the cells cancerous, such as the proclivity to keep reproducing after the point at which normal cells die off, and the avidity with which they absorb nutrients and grow. In some cases, the mutations are externally caused by such factors as tobacco, sun exposure, and other carcinogens. In any case, different types of cancer cells resemble one another in only a few respects, for example, in the sense that they can genetically shut off the programmed cell death feature than normal cells incorporate, and that they are greedier than normal cells. This has led to forms of treatment that work to some degree in most types of cancer.
In a previous installment which posted on October 8, I attempted to describe the current lay of the land in cancer treatment, touching briefly on some more recent developments, but focusing mostly on the improvements and refinements in the standard treatment forms, which are after all the treatments modalities employed in the great majority of patients. Those are surgery, chemotherapy, and radiation therapy. To recap briefly, I pointed out that each of these forms of treatment has been immensely improved since they were first introduced, and I noted the genuinely good results achieved in some of the most commonly-occurring types of cancer.
The differences between cancers affecting a single location can be highly significant, and teasing out these differences requires a level of investigation far more intensive than distinguishing between different bacterial pathogens. Researchers have to delve deeply into the structure of the individual cancer cells, down to the structure of the genetic material that determines the cancer’s behavior. Among the most promising developments in cancer research are tools that permit researchers to investigate the DNA of cancer cells, and also in some cases to alter the DNA of cells in the human immune system so that these cells are able to attack cancer cells. There tools are known by their abbreviations – CRISPR-Cas9 and CAR-T.
CRISPR-Cas9 stands for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9, if you want to know. Some bacteria have evolved a genome-editing technique which lets them capture snippets of DNA from invading viruses and use them to create DNA segments that help the bacteria recognize those viruses and similar viruses. The bacteria then use the Cas9 enzyme to cut apart the viral DNA, and this disables the virus. Researchers have learned to imitate this system in the lab. They are able to cobble together a small DNA segment that binds to a specific sequence of DNA in a genome, whether in a human cell or a cancer cell. The DNA segment also binds to the Cas9 enzyme, which can cut the DNA in the target genome. This technique holds enormous potential in altering the genome of cells in the immune system and enabling them to attack invaders that have been resistant to attack.
The Cas9 enzyme is not the only enzyme that could be used as a scalpel to carve up DNA. Another possibility is the Cpf1 enzyme. And there are variants of the Cas9 enzyme that may be more useful. The most widely used Cas9 enzyme comes from Streptococcus pyogenes, (SpCas9) and recognizes only about 10% of the places in the DNA sequence. A team of researchers at MIT has identified another Cas9 variant that might be more useful, in Streptococcus canis (ScCas9) which can hit almost half of the locations on the DNA genome.
MIT scientists hope to able to use their new CRISPR tool to carry out a more precise kind of gene editing. Some diseases can be treated by disabling the entire gene consisting of about a thousand base pairs, but others such as sickle cell anemia are caused by a mutation at a single location in the genome. This requires the ability to land at the exact spot and excise the single base that causes the disease.
There has been a good deal of controversy about using CRISPR-Cas9 to modify the human genome. It would be theoretically possible to use this technique to change human genetic characteristics. For example, DNA sequences that result in genetically-determined diseases might be able to be edited out. But the very idea of scientists creating a superior human subspecies in the lab gives many people, including yours truly, the creeps.
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The “CAR” part stands for ‘chimeric antigen receptor,’ and the “T” for T cells. By now everybody knows about T cells, those cells in our immune system that are supposed to protect us from harmful invaders. Those are the cells that are attacked by the human immunodeficiency virus (HIV) in people with AIDS, and the progress of the disease has usually been measured in terms of the patient’s T-cell level, because the virus attacked and disabled T cells. Well, cancer cells also attack and disable T cells, and the CAR-T strategy is an effort to reverse that process such that T cells can be modified to attack and destroy cancer cells.
The part that enables the T cells to do battle against the cancer cells is the CAR, the chimeric antigen receptor. Cancer cells have a protein on their surfaces which is classified as an antigen, meaning any molecule that can be recognized by the immune system as an invader. In the case of many cancers, the term “antigen” is a bit deceptive, because in fact the immune system often does not recognize the so-called antigen as an invader, permitting the cancer cells to survive and spread.
That’s where CAR comes in. In the CAR-T strategy, the T cells are modified so that they do recognize the antigen. They have been engineered with a receptor, the chimeric antigen receptor or CAR, which specifically recognizes the antigen on the cancer cell’s surface. Designing a receptor that will recognize the antigen is a highly complex feat, requiring precise knowledge of the shape and molecular structure of the antigen, so that antigen and receptor essentially lock together.
Once the T cells with the CARs on the surface encounter and bind with the cancer cells, the T cells move on to the task for which they are designed – attacking and destroying invaders.
So far, the most effective strategy for employing T cells to treat cancer has involved removing a large population of T cells from the patient, genetically modifying them outside the patient’s body so that they will recognize and combat cancer cells, and then reinfusing them. Once reinfused, the modified T cells will reproduce, retaining their genetic modifications, and join the battle against cancer cells. This strategy has the enormous benefit of avoiding the side effects that occur when the process of T-cell engineering using CTLA-4 antibodies takes place inside the body. These bio-engineered T cells, primed to recognize and attack cancer cells, are themselves a new generation of cancer-combating agents.
It has to be acknowledged that CAR-T therapy is likely to be very expensive. At a CAR-T summit a couple of years ago, participants were asked what they thought a justifiable cost for CAR-T therapy would be in the future. Forty percent thought it could cost between $100,000 and $250,000, and another 38% went for $300,000 to $500,000.
Let’s take a look at the remarkably large number of new cancer therapeutics that obtained FDA approval in the 12 months from August 1, 2017 through July 31, 2017.
- Adcetris (brentuximab vedotin, Seattle Genetics) is a conjugate consisting of a drug linked to a monoclonal antibody (mAb) which binds to cells present in the white blood cells of Hodgkin lymphoma patients causing death of the disease-causing cells. It is approved for the treatment of untreated classic Stage 3 or 4 Hodgkin lymphoma.
- Aliqopa (copanlisib, Bayer) is a kinase inhibitor which interrupts the P13K B-cell signaling cascade. It is approved for the treatment of relapsed follicular lymphoma after two prior systemic therapies.
- Azedra (lobeguane 1131, Progenix Pharmaceuticals) consists of a molecule analogous to norepinephrine linked with a radioactive iodine isotope (I-131). (We discussed this specific drug in the previous cancer piece.) Azedra is used to treat adrenal gland tumors that have norepinephrine surface receptors. The drug links to those surface receptors, conveying the radioactive material to the cancer cell. Azedra is approved for the treatment of unresectable (meaning that these tumors cannot be removed surgically) and metastatic adrenal gland tumors.
- Besponsa (inotuzumab ologamicin, Pfizer) is an mAb targeting the CD22 cell surface antigen. Besponsa is approved to treat relapsed or refractory acute lymphocytic leukemia.
- Braftovi and Mektovi (encorafenib and binimetinib, Array Biopharma) respectively block the activity of mutated forms of molecules dubbed BRAF and MEK. These mutated molecules signal cells to grow and divide out of control, and have the potential to become melanoma tumors. Braftovi and Mektovi are approved to treat unresectable metastatic melanomas that possess those mutated genes.
- Calquence (acalabrutinib, AstraZeneca) is a tyrosine kinase inhibitor of a specific type, the Bruton tki, which is a cancer-causing agent. Calquence is used to treat mantle cell lymphoma in patients who have gone through at least one previous treatment for some form of cancer of the blood.
- Erleada (apalutamide, Janssen) is an androgen-receptor inhibitor used to treat non-metastatic castration-resistant prostate cancer. (Castration-resistant in this sense means chemical castration, referring to patients who have been treated with some form of androgen antagonist, and not to patients who have actually been surgically castrated, with no effect on their cancer.)
- Idhita (enasidenib, Celgene/Agios) blocks the effects of a protein that is part of a cancer cell’s epigenome and helps the cancer cells to grow. It is used to treat patients with relapsed or recurrent acute myeloid leukemia (AML) with the IDH2 mutation. (Note, epigenetics, which we have mentioned from time to time, concerns molecules that are attached to but not part of the DNA of cells, and affect their growth and behavior.)
- Imfinzi (durvalumab, AstraZeneca) is a PD-L1 checkpoint inhibitor which was approved to treat unresectable Stage 3 non-small-cell lung cancer. (Checkpoint inhibitors were discussed extensively in the previous cancer piece.) It was recently demonstrated that treatment with Imfinzi resulted in a 32% lower risk of death in non-small-cell lung cancer than the previous standard of care. Before that, it was shown to ward off disease progression for about one year longer than placebo.
- Keytruda (premalizumab, Merck) is a PD-1 checkpoint inhibitor. It most recently received approval as a combination treatment for metastatic non-squamous non-small-cell lung cancer. It is also indicated for advanced melanoma, squamous cell cancers of the head and neck, Hodgkin lymphoma, urothelial carcinomas, some metastatic solid tumors, and cervical cancer.
- Kymriah (tisageniecleucel, Novartis) is a CAR-T agent, approved to treat non-Hodgkin lymphoma in patients who have failed two previous courses of treatment.
- Lutathera (lutetium 177 dotatate, Novartis) is another radionucleide linked to a molecule that is similar to somatostatin, which attaches to a tumor cell’s somatostatin receptors, delivering radiation to the tumor cell while sparing healthy tissue from the effects of radiation. Lutathera is approved for treating gastroenteropancreatic neuroendocrine tumors. This form of treatment increases the time to disease progression by a factor of six.
- Lynparza (olaparib, AstraZeneca) inhibits a mechanism in cancer cells that repairs the cancer cell’s DNA. The class name is PARP inhibitors; PARP stands for poly ADP ribose polymerase. Lynparza is approved for the treatment of recurrent ovarian cancer and BRCA-mutated HER2-negative breast cancer. (HER2 is human epidermal factor receptor 2)
- Mylotarg (gentuzumab ozogamicin, Pfizer) is directed against the CD33 cell surface antigen, damaging cancer cell replication. Mylotarg is approved for the treatment of newly-diagnosed acute myeloid leukemia (AML), and also relapsed or refractory AML.
- Opdivo (nivolumab, Bristol-Myers Squibb) is another checkpoint inhibitor, with ten FDA indications. The most recent was in August, 2018, for the treatment of patients with small cell lung cancer who had previously failed to respond to chemotherapy and had been considered essentially incurable. Among the 11% of patients who responded, 39% were still responding to treatment at 18 months.
- Tafiniar/Mekinist (dabrafenib/trametinib, Novartis) interrupts the MAPK cell-signaling pathway in cancer cells. It is approved for metastatic or unresectable melanoma with the BRAF gene and also for metastatic or recurrent non-small-cell lung cancer with the BRAF-v600E gene.
- Tibsovo (ivosidenib, Agios) is another drug targeting the epigenome of cancer cells. It is approved for the treatment of relapsed or recurrent acute myeloid leukemia.
- Verzenio (abemaciclib, Eli Lilly) is a CDK4 and CDK6 inhibitor, which affect the growth and division of cancer cells. It is approved for the treatment of HER2 positive and HER2 negative metastatic breast cancer.
- Vyxeos (daunorubicin/cytarabine, Jazz Pharmaceuticals) is a combination of two fairly well-established chemotherapy agents. Daunorubicin promotes the production of DNA-damaging free radicals, while cytarabine damages DNA by inhibiting DNA polymerase. It is approved for the treatment of newly-diagnosed acute myeloid leukemia.
- Yescarta (axicabtagene ciloleucel, Kite/Gilead) is a CAR-T agent, approved for treatment of non-Hodgkin lymphoma in patients who have failed two previous treatment courses.
It will not have escaped the astute members of the Gumshoe community that most of the approvals mentioned above were for cancer variants that are among the most difficult to treat. In many cases, the benefit that drug treatment delivered was modest, and many people question whether the benefit in terms of extended survival is worth the cost in terms of diminished quality of life. However, what this point of view misses is that there are cases where the benefit exceeds the downside by a huge margin.
Consider for a moment the results of a recent study, published October 20th in the New England Journal of Medicine. (Schmid P. N Engl J Med 2018 Oct 20. doi: 10.1056/NEJMoa1809615)
Tecentriq plus Abraxane in triple-negative breast cancer
In breast cancer, triple-negative refers to absence of two hormone receptors plus absence of human epidermal growth factor. Triple-negative breast cancer is especially difficult to treat because of the absence of those treatment targets. Fortunately, it is a relatively rare form of breast cancer; unfortunately, the survival rate in women hit by triple-negative breast cancer is far lower than for breast cancer in general.
The study in question enrolled 902 women with advanced metastatic untreated triple-negative breast cancer. Half were assigned to Abraxane (nab-paclitaxel, Celgene) monotherapy, and the other half were assigned to Abraxane plus Tecentriq (atezolizumab, Roche). Abraxane is an inhibitor of cancer cell division, and in that way slows the growth of the cancer cell colony. Tecentriq is a checkpoint inhibitor, a form of treatment that falls under the category of immunotherapy. (As we discussed in the “Lay of the Land” piece last month, checkpoint inhibitors chip away at the protections that cancer cells erect [checkpoints], permitting the patient’s own T-cells to go after the cancer cells and get rid of them.)
The women in the trial were particularly difficult to treat, since in a addition to their triple-negative state, their cancer had been untreated and had advanced to the point of metastasis.
In terms of overall progression-free survival, the difference between the two groups was modest. Progression-free survival was 5.5 months in the Abraxane group compared with 7.2 months in the women receiving Abraxane plus Tecentriq. But when patients with PD-L1 positive tumors were compared, the difference in overall survival between the groups was significant – 15.5 months for those receiving Abraxane alone versus 25 months for those on Abraxane plus Tecentriq.
However, even this was not the factor that caught the attention of the investigators as well as of the attendees at the meeting of the European Society for Medical Oncology in Munich, where the study was presented. What many found to be genuinely game-changing was what was called “raising the tail” of the survival curves. Although an increase in median survival of 25 months in patients with advanced metastatic cancer is by no means negligible, what was found to be truly remarkable is that some women continued to be entirely tumor-free at the end of the 25 months of follow-up. Remember that these patients had metastatic breast cancer of a type that is especially resistant to treatment. We can’t pronounce them “cured,” since it is not known whether their cancers might come back, and it is also at this time unknown whether they can safely stop the Tecentriq treatment. Follow up of this patient cohort continues.
Several cancer specialists who were not involved in the study concurred that these results were highly significant and would likely have an impact on the way breast cancer is treated. A question raised by some practitioners was whether women with similar forms of breast cancer might have access to combined therapy in advance of FDA approval.
Most of the news concerning new forms of cancer therapy is positive, or at least includes a hopeful note, as in, “yes, the improvement in outcomes between the patients treated with our new drug and those treated with the old-line chemo agent was very small, but remember that these were the most difficult-to-treat patients; in a more usual patient population we would likely have seen much better outcomes.”
In contrast, here’s a news item that not only has no hopeful notes, but sounds a genuinely dire warning.
A note of caution
It concerns the newly-approved CAR-T drug, Kymriah, (tisageniecleucel, from Novartis) and one patient, age 20, who had an aggressive form of leukemia. His treatment was the standard CAR-T procedure, which involved harvesting T-cells from his bloodstream and exposing them to the CAR-T agent in such a way that the T-cells would be modified to recognize and attack the cancer cells when they were reinfused into the patient’s circulation. But in the case of this patient, there was a miss-step. A single leukemic cell inadvertently came along with the T-cells, and exposure to the CAR-T agent caused genetic changes in the leukemia cell as well. These changes rendered the leukemia cell immune to attack by the genetically-modified T-cells. And the leukemia cell rapidly multiplied, leading to a condition in which the patient’s disease worsened. Examination of the leukemia cells showed that they were genetically identical, and all were immune to attack by the T-cells.
When this patient’s course of therapy started, the patient quickly showed signs of improvement and before long he was declared to be in remission. But as the genetically modified leukemia cells began to multiply, the patient relapsed. Ultimately, nine months after treatment started, this patient died.
This unfortunate incident is not so much an example of a treatment failure in an aggressive and difficult-to-treat disease, but an example of a treatment failure that ended up causing the death of the patient. The CAR-T drug essentially created the cancerous cell which, behaving as cancer cells are wont to behave, reproduced rapidly and killed the patient. Scientists at the University of Pennsylvania, where this occurred, confirmed that all of the leukemic cells in this patient were genetically identical, proof that they were descended from the original cell created in the CAR-T process. This is evidence that CAR-T is a powerful agent and needs to be monitored with maximum care.
A spokesperson from Novartis stated that Novartis has the means to ensure that leukemia cells are not harvested from patients in the CAR-T process, and that in 400 patients treated with Kymriah, no similar incidents had taken place.
Possible good news on the glioblastoma front
This is only a small glimmer of light. Glioblastoma, as most of us remember, is the form of brain cancer that carried off Senator John McClain. At best, it is exceedingly difficult to treat. Again, this news item concerns CAR-T treatment and the University of Pennsylvania. A group of ten heavily-treated patients with multi-focal, recurrent glioblastomas, was exposed to CAR-T treatment. Only about half of patients with glioblastomas survive more than 18 months after diagnosis, and in patients with the characteristics of patients in this study, survival is extremely poor even by those markers. The T cells modified in this CAR-T treatment were dispatched to track down epidermal growth factor vIII (EGFRvIII) cells attached to cancer cells, and all the patients had detectable circulating modified cells in their blood within the first month after infusion.
Of the ten patients in the study, seven lived longer than predicted based on the number of previous treatments they had undergone and the nature of glioblastoma recurrences. Three are still alive, and one of those three has achieved a stable condition and remains stable to date. In light of the overall dismal survival rates in patients with these characteristics, this is a bright spot.
Dr Daniel M. O’Rourke, the principal investigator said, “This is an early stage trial, but we are encouraged by the fact that the cells got into the brain, proliferated, and reduced the level of antigen with very little toxicity to the patients. We can build on this as a therapeutic option for these patients. It gives us clues on what to do next.”
“What to do next” likely means targeting additional antigens, other than EGFRvIII, and perhaps also using other existing drugs to overcome resistance in the tumors. These would likely be agents that target the immunosuppressive molecules in tumors, such as the checkpoint inhibitors that we have mentioned.
… and a bit of unequivocally good news
This concerns women with advanced BRCA-positive ovarian cancer. (BRCA, by the way, is not an abbreviation for anything – it is the designation of a pair of specific genes. Possession of the BRCA genes protects tumors from attack by the human immune system.) A randomized trial reported strongly positive results with Lynparza (olaparib, the PARP inhibitor from AstraZeneca mentioned above). After three years of treatment with Lynparza, 60.4% of the women in the trial remained alive and without disease progression, which compared with 26.9% of the women who were receiving standard treatment that did not include the PARP inhibitor.
The trial, SOLO-1, which was presented in October at the European Society for Medical Oncology, reported data on 391 patients. Women treated with Lynparza had a 70% reduction in the risk of death or disease progression. At this point, 41 months into the trial, the median time to disease progression in this cohort has yet to be reached. Perhaps even more impressive, therapy with Lynparza stopped after two years, but survival in the women who were treated with Lynparza remained stable, suggesting that the treatment effect persists after the treatment itself ceases.
How does this all add up?
The wise denizens of Planet Gumshoe should come to their own conclusions. But permit Doc Gumshoe to venture an opinion. First, the mainstays of cancer treatment are going to continue to be surgery, radiation, and chemotherapy, each of which have been made much more precise and effective than they were a relatively short time ago. If we define it as a form of treatment that targets one or another of the general characteristics of cancers, chemotherapy in particular has seen huge improvements in effectiveness as well as safety. It should no longer be denigrated with the term “poison,” nor should surgery and radiation be similarly denigrated as “cut” and “burn.”
Second, I have no doubt that you clever readers have noticed that the major winners in the race to get new cancer drugs to market are precisely those big players that we would expect to see in the top ranks. I won’t go back and name them now, but it should be no surprise.
And third, I venture to say that CAR-T has entered the mainstream, but CRISPR – whether using Cas9 or something else – has a way to go.
Meantime, a team of Australian scientists has discovered a protein, identified as Pax5, that organizes and stores DNA to ensure that cells will be able to receive genetic instructions to maintain health. The potential role of this interesting protein in cancer treatment will be the subject of much further investigation. Doc Gumshoe will be on the lookout for news.
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Many thanks for all your comments. I’m pondering where next to shine my light and would welcome your suggestions. Perhaps another look at Delta 8? And perhaps also at L-carnitine, the “miracle amino acid?” Best to all, Michael Jorrin (aka Doc Gumshoe.
[ed note: Michael Jorrin, who we like to call ”Doc Gumshoe,” is a longtime medical writer (not a doctor) who shares his mostly non-investing-related thoughts with the Gumshoe community a couple times a month. You can see all of his columns here.]