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Leukemia–going for the cure!

Chronic Myeloid Leukemia. Source: Paulo Mourao. http://bit.ly/14ZLZqA

Chronic Myeloid Leukemia. Source: Paulo Mourao. http://bit.ly/14ZLZqA

Both the 28 June 2013 issue of Science and the 27 June 2013 issue of Nature have articles or sections that feature discussions of new ways to treat or even cure various types of leukemia.

The human interest story about T-cell immunotherapy researchers in Science

The 28 June 2013 issue of Science contains an article by Science staff writer Jennifer Couzin-Frankel entitled “The Dizzying Journey to a New Cancer Arsenal”. It focuses on researchers who have been working in the engineered T cell adoptive immunotherapy project at the Perelman School of Medicine of the University of Pennsylvania. We featured a discussion of this project, which since August 6, 2012 has involved a collaboration with Novartis, in our September 12, 2012 article on this blog.

Ms. Couzin-Frankel’s article is a human interest story which especially focuses on Carl June, MD, and how he came to work on T-cell immunotherapy. This included how cancer had touched his own life, with the death of his first wife, Cynthia, in 2001. The article also focused on patients who were successfully treated with the therapy, including biotech company scientist Douglas Olson, and Emily Whitehead, who is now eight years old and achieved remission from what had been end-stage leukemia over a year ago.

As we discussed in our September 2012 article, the Penn group has been developing adoptive immunotherapy based on autologous T cells engineered with chimeric antigen receptors (CARs). Specifically, this involved a CAR with specificity for the B-cell antigen CD19, coupled with the T cell costimulatory receptor CD137 and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. (In the Science article, CD19 is referred to by its alternative name, 4-1BB.) These engineered T cells are designed for the treatment of B-cell leukemias, such as B-cell chronic lymphocytic leukemia (CLL). As discussed both in our 2012 blog article and in the 2013 Science article, Novartis has been collaborating with the Penn group in order to industrialize production of the autologous engineered T cells and their use in treatment of patients. Via the ability of Penn to patent and license its technology, the Novartis collaboration also provides a potential means to conduct clinical trials under FDA regulation, and thus to commercialize a form of adoptive cellular immunotherapy for the first time.

Nature’s special supplement on leukemia

The 27 June 2013 issue of Nature includes an entire Nature Outlook supplement on “Leukaemia”. The supplement–or at least the portion of it that consists of articles produced under Nature’s “full responsibility for all editorial content” is available free online to all.

The general theme of the special supplement is stated in the introductory article by science writer and editor Apoorva Mandavilli “While survival rates for some types of leukaemia have improved dramatically, this family of blood cancers remains a potentially fatal disease. Research in epigenetics, immunotherapy, and cell transplants offers hope. And leukaemia is proving a testing ground for the theory of cancer stem cells — leading to knowledge that could advance cancer research overall.”

The Nature Perspective on adoptive T-cell immunotherapy by Penn researchers Levine and June

Included in the supplement is a short Perspective on CAR-based adoptive T-cell immunotherapy by Drs. Bruce L. Levine and Carl H. June of the Perelman School of Medicine at the University of Pennsylvania. It is entitled “Assembly line immunotherapy”. According to this Perspective, CAR technology [unlike the earlier tumor infiltrating lymphocyte (TIL) technology] enables researchers to ” efficiently produce large populations of T cells, approximating the mass of T cells in the human immune system”.

Drs. Levine and June further assert that by “using equipment and facilities developed for blood banks and stem-cell laboratories, and by automating production”, it will be possible to make CAR-based adoptive cellular immunotherapies (ACTs) widely available. Thus leukemia treatment may be on the brink of a revolution such as the auto industry experienced in recent years in moving from manual assembly lines to robotic automation.

Despite the issue of the pharmaceutical industry and regulatory agencies such as the FDA and the European Medicines Agency being geared to developing drugs, not individually-prepared cellular therapies, Drs. Levine and June cite the case of  organ, bone-marrow, and stem-cell transplants. These modalities were seen as exotic a few decades ago, but are now utilized in treatment of tens of thousands of people. The authors thus envision that ACT may also eventually be scaled up to treat the large numbers of patients who might benefit from this type of therapy. However, this will require innovation in regulatory agency oversight, and in the means by which the pharmaceutical industry might commercialize such individualized technologies. As we discussed in our September 2012 Biopharmconsortium Blog article, Novartis and Penn are leading the way.

Moving toward cures for chronic myeloid leukemia–Dr. Charles Sawyers’ Perspective

Another Perspective in the special supplement is authored by Charles L. Sawyers, M.D. [Chair, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer (New York, NY), and Howard Hughes Medical Institute]. The Perspective, entitled “Combined forces”, focuses on chronic myeloid leukemia (CML). The first targeted kinase inhibitor for cancer, imatinib (Novartis’ Gleevec/Glivec) was initially approved for treatment of CML.

In our October 25, 2010 article on this blog, we discussed the classic proof-of-concept clinical trial that helped launch imatinib toward FDA approval. As we discussed in that article, Dr. Sawyers was a key leader of that trial. He was a co-recipient–with Drs.  Brian J. Druker and Nicholas B. Lydon, of the 2009 Lasker~DeBakey Award for Clinical Medical Research for his work on treatment of CML.

As we discussed in our Octotber 2010 article, imatinib is highly specific for the BCR-ABL fusion protein [which is generated as the result of the translocation that produces the Philadelphia (Ph) chromosome, the characteristic genetic abnormality of CML], as well as two other protein kinases. CML patients who are initially successfully treated with imatinib may experience resistance to that drug. As a result, two second-generation kinase inhibitors–dasatinib (Bristol-Myers Squibb’s Sprycel) and nilotinib (Novartis’ Tasigna) were developed to target imatinib-resistant mutated BCR-ABL proteins, and thus successfully treat imatinib-resistant CML. More recently–in September 2012–as mentioned in Dr. Sawyers’ Perspective, another second-generation agent, bosutinib (Pfizer’s Bosulif), has reached the market. A still newer agent, ponatinib (Ariad’s Iclusig) was approved in December 2012, under the FDA’s Accelerated Approval Program. Ponatinib is of special interest, since it  targets the T315I mutation, which confers resistance to all the other four targeted CML drugs.

In Dr. Sawyers’ Perspective, he discusses how oncologists might use the current armamentarium of targeted drugs for CML to move toward a cure for the disease. Resistance to imatinib occurs because of selection for resistant mutants of BCR-ABL . Second-generation agents inhibit BCR-ABL kinases with these mutations, thus restoring disease remission. The current armamentarium of kinase inhibitor drugs for CML covers all known resistance mutations; however, no single drug can prevent all forms of resistance.

The current paradigm for treatment of CML has been to start with imatinib, and keep treating with that agent until the patient develops resistance to that drug and disease recurs. Then the physician treats with one of the second-generation agents, which typically produces disease remission. However, this sequential treatment can select for cells with BCR-ABL molecules that contain multiple mutations, which will be resistant to all kinase inhibitors. (See a 2007 report by Dr. Sawyers and his collaborators demonstrating the hazard of sequential therapy with imatinib followed by dasatinib.)

Because the second-generation agents dasatinib and nilotinib are more potent than imatinib, they were approved for frontline therapy of CML instead of imatinib, subsequent to the publication of Dr.Sawyers’ 2007 article. They were approved for frontline therapy because of their superior clinical outcomes in head-to-head comparisons against imatinib. (Bosutinib and ponatinib are newer, and have not yet received frontline therapy approval.) However, Dr. Sawyers counsels caution, since  dasatinib and nilotinib have been studied for only 3–4 years compared with the 8–10 years of data that have amassed for imatinib. Thus replacing imatinib with one of these agents might still result in development of resistance down the road.

Dr. Sawyers postulates that Instead of focusing on which individual drug is best as a monotherapy, it is time for researchers to consider whether it might be better to use combination therapy with multiple kinase inhibitors instead of sequential therapy. Extrapolating from the experience with single- versus multi-agent therapy for tuberculosis and HIV/AIDS, a combination of two or three ABL inhibitors with non-overlapping BCR–ABL mutation resistance profiles would almost certainly prevent the emergence of drug resistance. This is particularly true in the light of ponatinib’s success against T315I.

In a recent French study cited by Dr. Sawyers, researchers found that patients with the best responses to treatment with imatinib alone (no BCR–ABL detectable for more than two years) may no longer need any kinase inhibitor drugs at all. In this study, 40% of patients had not relapsed after 18 months. This raises the possibility that these patients may be cured of their disease.

Dr. Sawyers hypothesizes that since next-generation BCR-ABL inhibitors have greater potency in clinical trials, and since two-drug combinations are superior to monotherapies in preclinical studies, upfront therapy with either a second-generation inhibitor or with a combination therapy may result in even higher percentages of patients who experience elimination of all CML cells.

Even though these more potent treatments would be even more costly than imatinib therapy, if these treatments are curative, their long-term cost will be lower than the current treatment. Therefore, they might be both medically and economically advantageous, as well as giving cancer patients what they really want–a cure.

Meanwhile, in the 18 July 2013 issue of Nature, Drs. Natalia L. Komarova (University of California Irvine, Irvine CA) and C. Richard Boland (Baylor University Medical Center, Dallas TX) published a News and Views article discussing recently published mathematical models that predict that combination therapy is more effective than sequential treatment in preventing drug resistance in cancer. These mathematical models were developed especially for treatment of CML and the solid tumors melanoma, pancreatic cancer, and colorectal cancer. But these types of models may apply to all cancers for which targeted therapies have been or are being developed.

Moving toward cures for chronic myeloid leukemia–the Novartis 27 June 2013 white paper

Bound with the Nature Outlook supplement on leukemia–immediately following the Levine & June article on adoptive immunotherapy–is a white paper by Novartis researchers (Szczudlo et al.), entitled “The Novartis research vision and approach for treating patients with chronic myeloid leukaemia”. Unfortunately, since this “sponsor feature” was not written under Nature’s “full responsibility for all editorial content”, this white paper is treated almost as an advertisement. It is not available in the online version of Nature, or anywhere else online. Perhaps Novartis will make this valuable white paper available online in the near future. As with other published reviews in scientific journals (and unlike advertisements), this white paper is signed by its authors, and has reference citations.

The subject of the white paper is developing approaches that will enable CML patients on tyrosine kinase inhibitor (TKI) therapy to safely and effectively suspend their drug therapy, while maintaining minimal residual disease (MRD) levels that are either undetectable or below the level at which there is a risk of progression to more advanced phases of disease. Such a condition is known as “treatment-free remission” (TFR).

The research that is the focus of the Novartis white paper does not involve treatment with combination therapies, but monotherapy with nilotinib (Novartis’ Tasigna). The TFR-focused clinical trials with nilotinib are made possible not only by the potency of this agent, but also the development of new diagnostic assays for level of residual disease. Traditional diagnostics for CML have been based on achieving a “complete cytogenetic response” (CCyR). A CCyR is defined as the state in which there are so few Philadelphia chromosome positive (Ph+) cells in a patient’s blood or marrow that they are undetectable by this assay.

The new diagnostic assays involves measuring levels of BCR-ABL messenger RNA (mRNA) transcripts using a real-time quantitative polymerase chain reaction (RQ-PCR). The results of these sensitive assays are reported as major molecular response [MMR–a 3-log reduction in BCR-ABL levels from the international scale (IS) baseline; molecular response ≥ 4.0 logs (MR4); and molecular response ≥ 4.5 logs (MR4.5)].

Using these assays, researchers are participating in new Novartis-sponsored clinical studies of

  1. patients who had previously been treated with imatinib, without achieving MR4.5, and who were then switched to nilotinib.
  2. patients treated do novo with nilotinib.

The strategy is to maintain patients on nilotinib who have achieved MR4.5 for one year at that level, and then discontinue drug treatment. These patients continue to be monitored, and must maintain ≤ MR4 in order to remain free of nilotinib treatment. Those who exceed this threshold will be put back on nilotinib. So far, in earlier studies, patients on imatinib or niolotinib who were ≤MR4 off-drug and who then exceeded this level, when put back on their drug went back to deeper levels of molecular response to therapy, and showed no drug resistance. These clinical trial protocols therefore appear to be safe.

For more information about the above clinical trials, see ClinicalTrials.gov, clinical trial number NCT01784068 and NCT01698905. Both of these trials are recruiting patients.

The Novartis white paper does discuss a different kind of combination therapy than the ones proposed by Dr. Sawyers–combination therapy with a potent TKI such as nilotinib and an agent that specifically targets leukemic stem cells (LSCs). TKI-insensitive leukemia stem cells have been implicated in the persistence of MRD, and LSCs could contribute to the re-emergence of disease following suspension of TKI treatment.

Novartis and its collaborators are now testing TKIs in combination with Novartis’ experimental agent sonidegib (LDE225). Sonidegib is an inhibitor of the hedgehog (Hh) pathway. Aberrant activation of the Hh pathway has been implicated in the activity of LSCs and of other types of cancer stem cells. A poster session that described an in vitro study of a combination of sonidegib and nilotinib in CML was presented at a scientific meeting in 2010. Sonidegib (which is also known as erismodegib) has also been undergoing preclinical studies as a potential inhibitor of prostate cancer stem cells.

Conclusions

We recommend the 28 June 2013 Science article by Jennifer Couzin-Frankel, and the special supplement on leukemia in the 27 June 2013 issue of Nature for your late summer reading. It is heartening to see that at least some researchers are moving towards cures for various types of leukemia–with potential implications for development of cures for other types of cancer.

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