[ed note: Michael Jorrin, who I like to call “Doc Gumshoe”, is a longtime medical writer (not a doctor) who shares his thoughts with us from time to time, generally on non-financial topics in health and medicine (as today, though, he mentions a couple publicly traded companies). His words and opinions are his own.]
The needle in Doc Gumshoe’s handy Trend Indicator points unwaveringly towards Precision Medicine. This is possibly a public-relations-motivated bandwagon, and if you citizens of Gumshoe Republic have been paying attention, you know that recent jumpers-on have included the highest in the land. This is not to say that Precision Medicine has no merit other than its PR value, only that the nomenclature begs the question. Precision Medicine is obviously good, and that suggests that the rest of medicine – by implication imprecise? – is groveling in the mud.
There are other ways to describe this research avenue – individualized or personalized therapy, molecular targeted therapy, genomic-based therapy – which do not set up an automatic “good vs bad” distinction. The objective of these developing cancer therapies is to identify and target the vulnerabilities in the specific cancer in a specific patient. It does not take anything away from the immense potential of individualized therapy to point out the success of the therapies that have successfully targeted the behaviors that most types of cancers have in common. These were discussed in the first installment, “Cancer Care: Where Are We and Where Are We Heading,” which was posted a couple of weeks ago, and which you can see here. Among these are the characteristics that cancers grow more quickly and need somehow to induce new blood vessel growth to provide needed nourishment, and also that cancer cells will replicate endlessly. Drug therapies have been developed that target both of those behaviors, and these therapies have been hugely successful. They are not “Precision Medicine,” but neither are they some inferior, imprecise form of medicine, deserving of the scorn of the media and the public.
We’ll take a look at some of the approaches to individually-targeted therapy and some of the agents, some already on the market, but most at various stages of development. Many of these drugs look quite promising, both from the standpoint of the benefit that they may bring to cancer patients and also the profits that they may lavish on developers and investors. The clues about these agents’ potential come in the form of clinical trial results. But I need to warn you that in many cases, these clinical trial results appear a bit dim. They are expressed in terms of additional survival time in the patients taking the new drug, and quite often the additional survival is a matter of months. Critics, whose numbers are legion, point out that giving a few more months of misery to a terminal cancer patient is no great gift. However, there’s a reason why those results are often discouraging.
Why clinical trial results with new cancer drugs are often less than stellar
The ideal scenario for a drug developer is to find an agent that treats a disease or condition for which there are no known effective interventions. In such a case, the developer announces a clinical trial and is immediately overwhelmed with candidates, since even if the patient gets assigned to a placebo, it’s no worse for the patient than the current situation in which there is no treatment at all. And in most cases in such clinical trials, patients in the placebo arm are permitted to switch to the treatment arm after a certain period, at which point they get a drug which would not otherwise be available to them. For potential drugs that treat some diseases/conditions, there are also other options. In the case of a drug to treat hypertension, it may be possible to recruit newly-diagnosed patients to a clinical trial, even a placebo-controlled trial, because the effectiveness of a drug to lower blood pressure becomes apparent relatively quickly, so clinical trials are not over-long, and the patients in the placebo arm are not exposed to undue risk.
But with a cancer drug, the restrictions present a colossal hurdle. In the first place, it’s obviously impossible – or at least completely unethical – to put cancer patients on a placebo, so there’s no question of demonstrating efficacy in comparison to placebo. In the second place, there are many established forms of treatment for almost every form of cancer, and even if the treatment has mixed results, very few patients would agree to a completely experimental treatment for a disease that could kill them in fairly short order, when there are treatment forms available that have at least a reasonable chance of success. So there are very, very few clinical trials of new drugs that are able to enroll newly-diagnosed patients.
In most cases, cancer trials initially enroll patients in whom established forms of treatment have failed. Often, these are patients in whom a cancer that originated in one site has metastasized to another site or to multiple sites. The new drug will seldom be used by itself, but will be combined with another, more established drug.
Positive results in these cancer trials usually consist of only a few months longer survival than in patients treated with established drugs. Both the FDA and the EMA (European Medicines Agency, which is the FDA equivalent in Europe) recognize these as positive results and approve the drug, but that does not mean that the drug will be widely-used. An example is a promising drug, Zaltrap (ziv-aflibercept) from Regeneron. Zaltrap improved survival by only 1.4 months in patients with metastatic colorectal cancer as compared with Avastin (bevacizumab), from Genentech. Memorial Sloan-Kettering decided not to use it, because it costs about twice as much per month ($11,000) as Avastin. But that doesn’t mean that in recently diagnosed, early stage cancers, drugs like Zaltrap might not be a significant improvement. Currently, Avastin is approved for use in other cancer sites besides colorectal cancer – glioblastoma (a highly malignant form of brain tumors), non-small cell lung cancer, and metastatic kidney cancer – and is being studied in many other types of cancer. Zaltrap is also being studied in more than 80 clinical trials, in several types of cancer, but the way forward is not clear.
What cancer drug developers hope is that they come up with an agent that demonstrates better results than whatever else is out there, even if it’s only a few more months of overall survival in these exceedingly difficult-to-treat patients. Modest benefit in the most difficult patients can then provide justification for using that agent in patients with less advanced disease, frequently in combination with another drug, or after some other first-line therapy has been employed – what’s termed “adjuvant” therapy – or sometimes in advance of first-line therapy, such as in the attempt to shrink a tumor so that it can more easily be surgically removed. This last is called “neoadjuvant” therapy. The ultimate goal of drug developers is, of course, to have their drug recognized as the first-line therapy of choice. This does not happen overnight, but it has been known to happen.
What are the goals of “Precision Medicine”?
Obviously, the ultimate goal is to treat cancer more effectively – the question is, “How, exactly?” The wide-angle answer is that this approach proposes to base cancer treatment on cause rather than on location; meaning that instead of classifying cancers by the organ systems that they affect, Precision Medicine expects – ultimately! – to be able to pinpoint the genetic cause of many or most cancers and to develop treatments that target the specific genetic cause and, in some way block or inhibit its cancer-producing effects.
In promoting this approach, there’s a good deal of supercilious characterizing of location-based cancer treatment as imprecise and somehow behind the times. This needs to be viewed with skepticism. It will be a long, long time before oncologists ignore the location of a cancer in planning treatment: regardless of gene-sequencing, malignant melanomas will be treated differently than lung cancers.
But the Precision Medicine Initiative seeks to accomplish genuinely important objectives: essentially, by means of a proposed cohort of a million or more volunteers, statistically valid correlations will presumably emerge linking specific genomic sequences with specific cancers. This is something that Big Data can undeniably do, given enough time and enough money – and enough volunteers, of course. If robust correlations are found, it may be possible to make statistically valid assumptions about causality; this has already happened with several types of cancer, e.g., melanomas in patients with a mutated BRAF gene, and breast cancer in women with BRCA1 or BRCA2 genes or with particularly active HER2 receptors. In turn, those assumptions about causality have led to major treatment advances.
And what are they looking for?
Most of our genes don’t give a hoot about cancer, but among them there are heroes and villains. The heroes are the tumor suppressor genes, which identify cancerous cells early on and initiate processes that lead to their destruction, such as mobilizing the immune system. The villains are the driver oncogenes, which can signal cells to multiply and grow endlessly, until they overwhelm the entire organism, occupying space, stealing nourishment, interfering with necessary function, and destroying tissue. But the driver oncogenes can also initiate the cancer process by inhibiting the action of the tumor suppressor genes, or by interfering with the process that guides apoptosis – programmed cell death. Without apoptosis, normal cells can become cancerous.
A bit more specifically, here are some targets of genomic analysis:
- Abnormal gene mutations can be spotted in a total or partial gene sequence and statistical associations with cancers may emerge which permit forming a conclusion; i.e., this specific genetic mutation causes this specific cancer.
- The number of copies of specific genes in a tumor can be measured by means of a process called Fluorescence In Situ Hybridization (FISH); this provides information about gene duplication within a tumor.
- Gene translocation can be identified. This occurs when chromosomes break apart and rejoin, such that genes that are normally far apart are found in close proximity, with potentially malign consequences.
- Protein biomarkers in a tumor can be measured with approximate accuracy through immunohistochemistry, which can provide useful therapeutic information.
These analytic procedures can be used in the aid of finding the most effective drug as well as avoiding drugs that are less likely to be effective, either for the individual patient or for the specific cancer. In turn, a drug could be effective because it targets a specific type of cancer with known biomarkers, or because it targets an individual’s specific genetic abnormalities. In other words, genomic analysis would be carried out both in the cancer patient and, separately, in the cancer cells found in that patient.
An example of a cancer resulting from gene translocation is chronic myelogenous leukemia (CML), a disease which formerly was almost always fatal within about five years – formerly, that is, until the development of imatinib (Gleevec, from Novartis), which increases mean survival in CML patients to more than 20 years. Since CML mostly affects persons in their sixties, this amounts to conferring a normal life span in these cancer victims. Imatinib targets and disables the translocated driver oncogenes in CML; however, determining whether a patient is a candidate for imatinib requires sequencing of the translocated genes.
Genomic sequencing in the search for oncogenes is indeed highly promising, and the goal is not totally out of sight. It’s likely, based on analysis done so far, that the number of driver oncogenes is not enormous – perhaps only a few hundred – so continuing investigation will almost certainly continue to add to the number that have already been identified. But developing agents that will target and inactivate these genes is another matter altogether – first the oncogenes must be identified, then the drug developers have to figure out a molecule that can prevent these genes from doing their damage. The success of imatinib/Gleevec, which also can be used to treat other cancers, has not yet been matched by other agents.
Some promising approaches to treatment: the CAR-T strategy
Just to get it over with, the “CAR” part stands for ‘chimeric antigen receptor,” and the “T” for T cells. By now everybody knows about T cells, remembering that T cells are those cells in our immune system that are supposed to protect us from harmful invaders – those were the cells that were attacked by the human immunodeficiency virus (HIV) in people with AIDS, and the progress of the disease was usually 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.
Sounds simple, right? Conscript the T cells, enlist them in the battle against cancer, boost their morale with patriotic songs, and victory will soon follow.
Of course, it’s not quite so simple. 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.
Or, at least, that’s the proposed mechanism of action for many cancer drugs now under development. There have been some amazingly successful cases in which patients with seemingly terminal cancers, in which no treatment had worked, have received therapy based on engineered T cells and come out cancer free. Some of these treatments have been based on some previously-known mechanisms. For example, a protein called cytotoxic T-lymphocyte antigen 4 (CTLA-4), which protrudes from the surface of T cells, is thought to damp the response of T cells to cancer cells, and treating patients with antibodies to CTLA-4 has resulted in dramatic cancer remissions and even cures, although sometimes accompanied by horrendous side effects.
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 are themselves a new generation of cancer agents.
Cancers where CAR-T therapy has been used successfully to date
This approach has been amazingly successful in cancers such as acute lymphoblastic leukemia (ALL) and also chronic lymphocytic leukemia (CLL). Promising results have also been reported in some lymphomas. Several small trials have been conducted, as is common with experimental cancer treatments, in patients who had basically run out of options. In advanced ALL patients in whom no other treatment had worked, CAR-T therapy has resulted in many patients becoming entirely cancer-free, and many of these continue to be cancer-free to date. These small trials have been so successful as to attract hordes of pharmaceutical companies to explore this strategy.
One of the pharmaceutical companies that is out in front is Novartis (NVS), which was awarded breakthrough status by the FDA on July 7 2014 for its CAR-T agent CTL 019, which it is developing in collaboration with the University of Pennsylvania. In October, they announced results of a study in children and young adults with recurrent or refractory ALL, in which 36 of 39 patients attained complete remission. Novartis is a cancer powerhouse, with nine patented cancer drugs besides Gleevec, and many more in various stages of development.
Another frontrunner is Juno Therapeutics (JUNO), which has a CAR-T candidate dubbed JCAR015 in clinical trials, conducted in collaboration with Memorial Sloan-Kettering. Adults with recurrent or refractory ALL were treated with JCAR015, and the trial resulted in complete remission in 14 of 16 patients. Perhaps as a result of these results, JCAR015 was granted orphan drug status by the FDA on November 18, 2014. JCAR015 targets CD19, which is present on B cells that are involved in the ALL disease process. In order to assure a reliable supply of the agent, Juno is expanding to construct its own facility for the manufacture of their agent, rather than relying on contract manufacturers to supply their needs for clinical trials. And they have 10 more agents that they are planning to get into clinical trials in the next year or so.
Kite Pharma (KITE) is another strong contender in this arena. Their lead drug, KTE-C19, demonstrated strong results in a small trial in 15 patients with diffuse large B-cell lymphoma, which is a subset of non-Hodgkin’s lymphoma. Of those 15 patients, 8 were in complete remission and 4 in partial remission. As a result of this trial, KTE-C19 was given orphan drug status by the European Medicines Agency. Interestingly, Kite employs a retroviral vector to engineer T cells for this agent. The effect of viruses on T cells also appears to be a part of the mechanism of action of Pfizer’s T-Vec, which we discussed in the previous Doc Gumshoe piece on cancer. Kite has five more trials with KTE-C19 planned for 2015, as well as several trials with other candidate anti-cancer drugs that employ related mechanisms. Kite has recently teamed up with the Tel Aviv Sourasky Medical Center’s Prof. Zelig Eshhar to advance their research in this treatment area. And Amgen (AMGN) is partnering with Kite in the development of CAR-T agents.
Yet another contender is bluebird bio (no capital letters in its name!), which is collaborating with Celgene (CELG) and the Baylor College of Medicine to develop CAR-T agents. No specific agents have emerged, but the collaboration is typical of what’s going on in the field. A major pharmaceutical company, in his case Celgene, teams up with a small biotech that has strong credentials in advanced research, and an academic institution is in the mix as well. The lead bluebird product to date is a treatment of beta-thalassemia, which is a blood disorder resulting in insufficient hemoglobin production and consequent problems with transporting oxygen in the bloodstream. The mechanism it uses is autologous stem-cell transplantation, meaning that stem cells are engineered outside the patient’s body and then reinfused, a technique closely similar to CAR-T therapy. The as-yet-unnamed bluebird CAR-T initiative intends to treat solid tumors as well as hematologic cancers.
I could go on and on, but here’s another: two small biotechs, Interexon (XON) and ZIOPHARM (ZIOP) (yes, this one’s all caps) have partnered with M. D. Anderson in Houston, with the plan of developing five CAR-T agents, using what they are referring to as a “non-viral gene integration platform.” The partnering consists of $50 million payments from each of the two biotechs to support M. D. Anderson’s oncology research. The means they propose to use to modify the T cells is an engineered cytokine, based on an interleukin, IL-12. We need to note that other cytokines, namely IL-6 and interferon, have been used to attempt to tinker with T cells, with decidedly mixed results: the patients showed marked improvement, but the adverse effects were ghastly. In those cases, the cytokines were given to the patients with the expectation that the T cells would be modified internally; Interexon and ZIOPHARM (from what I can tell) are proposing to follow the currently-accepted method of removing the T cells, engineering them, and then reinfusing them. Their expectation is that their CAR-T therapies would be effective in a wide range of cancer types. There’s reason for optimism here; after all, M. D. Anderson is one of the two top cancer centers in the U. S.
Checkpoint strategies: PD-L1 & PD-1
The way this works is that T cells carry a protein that promotes programmed cell death, dubbed PD-1 (think Programmed Death One); this is one way that they attack tumor cells. In opposition, tumor cells carry a protein that links to and disables the PD-1 protein on T cells, dubbed PD-L1. Antibodies to this link can restore the T cell’s immune function, and a number of agents that employ this mechanism have recently won FDA approval. These include Merck’s (MRK) Keytruda (prembrolizumab), and Bristol-Myers Squibb’s (BSM) Opdivo (nivolumab). Other Big Pharma outfits are on the case, including Pfizer (PFE), which is working with Merck KgaA on a PD-1 inhibitor that will target some major cancers – kidney, bladder, and lung cancer.
Agents that target the PD-1/PD-L1 interaction enhance the tumor-fighting activity of T-cells with mostly acceptable side effects, in contrast with agents that employ the CTLA-4 pathway, such as Yervoy (ipilimumab), which triggers immune-related toxicities. The checkpoint inhibitors are thought by some to be good candidates for first-line therapy, probably in combination with drugs that inhibit tumor vascularization or cancer cell replication. That being said, these strategies have not excited the interest of the wider clinical community as much as the CAR-T therapies have done, probably because the CAR-T therapies seem to hold out the hope of results that might actually be termed cancer cures, which is to say, complete remission with no remaining trace of tumor burden.
… and that’s not all!
Another mechanism for recruiting the cancer-fighting capacity of T cells is a pathway called the bi-specific T cell engager, or BiTE. An agent targeting this pathway, blinatumomab, was developed by the biotech Micromet AG. This outfit was purchased by Amgen (AMG) for $1.2 billion in order to latch on to this promising drug, which was approved by the FDA on December 3, 2014. BiTEs, unlike other T cell strategies, bind to both the tumor cell and the T cell, forming a link, and thereby inducing the T cell to release tumor-fighting cytokines. Blinatumomab, now trade-named Blincyto, is approved for acute lymphoblastic leukemia (ALL) and also non-Hodgkin’s lymphoma.
Finally, Pfizer’s Ibrance (palbociclib), which mobilizes the T-cell army through kinase inhibition, was approved by the FDA based on Phase 2 data on February 3, 2015. It is indicated for first-line treatment (with letrozole) of breast cancer in women whose cancers respond to estrogen receptors, but do not express the HER2 gene. The indication is contingent on continuing positive trial data; however, it points to a clear clinical need and the strength of the data to date.
The overall picture is undeniably positive, not to say rosy. But the road ahead will certainly have potholes and possibly be littered with large rocks. Cancer is just about the trickiest of all adversaries. Those little tumor cells are doing everything they can to evade detection and survive. Even after the cancer detectives do their meticulous genome sequencing, the cancer cells may mutate, requiring continued efforts to stay ahead of the game.
And there will always be side effects. The adverse events / side effects that emerge early in the course of treatment, as with engineering T cells with CTLA-4, IL-6, or interferon, tell the clinician to stop and try something else. But tinkering with the immune system in any way could have consequences down the line – consequences that might take years to emerge.
Another factor that will need to be considered is the cost. Even though the goal of drug development is to create drugs that can be used against a number of different cancers, the likelihood of coming upon a drug that will just “cure cancer” is pretty small. Individual cancers in individual patients will need to be characterized, and, yes, the cost of genomic sequencing has plummeted in recent years, but the individualization of treatment – the very premise of “precision medicine” – will be very expensive. This may tilt some payers, and some governments, away from some of the most promising therapies.
On the other hand – and there’s always another hand – one of the current trends that points to lower costs is the current movement towards biosimilars. Doc Gumshoe preached about that in a previous piece. The biosimilar tide is rising, and it points to more treatment being available to more patients. The presumption with biosimilars is that since they are chemically very, very close to the originator drugs, they will have similar efficacy and safety. The regulators, in the US and Europe, seem to think so. But the proof that they really behave the same will emerge as they are adopted, which I’m sure they will be.
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It’s very hard to maintain a light tone while writing about cancer. In the minds of nearly everyone on the planet there lurks a fear of cancer. Might this symptom that we’re experiencing right now be the dreaded Big C? In the words of the poet W. H. Auden, “That spot on your skin is a shocking disease.” We accept mortality, but not that way.
When I was describing the kinds of patients that were likely to be enrolled in the clinical trials of new cancer drugs, the repellent phrase “hopeless cases” came inevitably to mind. “Hopeless cases” is linked, also inevitably, with another repellent phrase, “miracle cures.” Doc Gumshoe’s article of faith is that there are no hopeless cases. Patients whose chances of survival were thought to be miniscule have responded to treatment and gone on to enjoy many additional years of life and health. And, similarly, the treatments that conferred those additional years of life on those patients were not “miracle cures.” They were the result of diligent, painstaking, and genuinely inspired investigation by a community of researchers and clinicians that continues to pursue the goal of – shall I dare say it? – curing cancer.
Doc Gumshoe will continue to watch new cancer treatments and keep you posted.