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Eric Rosenthal Reports | A Personal Remembrance of Two Giants of Oncology: Jim and Jimmie Holland

James F. Holland, MD, one of the pioneers of combination chemotherapy and cancer cooperative group research, died at the age of 92 on March 22.  His wife, Jimmie C. Holland, MD, who was considered the founder of psycho-oncology, predeceased him by three months on Christmas Eve at age 89.

Jim was Distinguished Professor of Neoplastic Diseases at the Icahn School of Medicine at Mount Sinai in New York, and Jimmie was Wayne E. Chapman Chair in Psychiatric Oncology and attending psychiatrist at Memorial Sloan Kettering Cancer Center.

Photo 1.0: In the 1950s James (Jim) F. Holland and colleagues were considered the  “cowboys” of chemotherpy.

I knew both Jim and Jimmie, had interviewed them individually numerous times over many years, and considered them friends.  They both continued to work and contribute to their fields until the end, and always had new and interesting information to share.

I first met Jimmie in 1990 when I was chairing a meeting of a group I had founded, the NCI-Designated Cancer Centers Public Affairs Network, at MSKCC and our steering committee was treated to attending grand rounds with Jimmie Holland.  Several years later I was introduced to Jim.

At dinner a few years ago hosted by Stand Up To Cancer in honor of the PBS documentary series, “Ken Burns Presents Cancer: The Emperor of All Maladies,” Jimmie and I sat together and chatted most of the evening.  Later on, I thanked Jim for lending me Jimmie as my girlfriend. “As long as you’re not her boyfriend,” he responded with the wit and good humor that characterized him almost as much as his outspoken manner and colorful neckties.

When I began writing a series last year for MedPage Today about pioneers in oncology, my first call for an interview was to Jimmie, who had been encouraging me for many years to write a book about the cultural or social history of cancer.  She had promised to write the preface.

For the MedPage series I told her that I wanted to arrange separate interviews with her and then Jim over the next few weeks.

She replied that she thought it wise to start with Jim because of several health issues he’d been dealing with, and I took her advice.

A few months following publication of Jim’s profile, I called Jimmie again about scheduling a time to talk.   She did not respond immediately and finally replied that I should contact her again in several weeks.

When we spoke, she said that she had recently undergone surgery after developing a bilateral femoral arterial emboli, and how the experience—one of the few medical issues she had encountered during her long life–had enhanced her understanding of how so many of her cancer patients had felt.  She was, after all, the psychiatrist who had pioneered a field based on how people cope with a devastating disease rather than dealing with mental illness.

Our conversation, however, only lasted a short time since she was fatigued from her condition, so we rescheduled for November when she was up to speaking at length and about some things she had never discussed before.

That interview, which may have been her last, was published a month before she died in her Revolutionary-era home in Scarsdale, NY, surrounded by her family.

I wrote to Jim expressing my condolences but did not receive a reply.  Then in March during an interview with Larry Norton, MD, who considered Jim a mentor and was a longtime colleague of Jimmie’s at Memorial Sloan Kettering, we discussed how Jim was following the loss of Jimmie.  Larry said he had written to Jim several times but hadn’t heard back.  That conversation was days before learning about Jim’s death at home from respiratory failure.

During their early years in Buffalo, N.Y., during the 1950s, Jim was chief of medicine B at Roswell Park Cancer Institute, and Jimmie was head of psychiatry at Erie County Medical Center. During an 8-year period she also had five children taking 6-month leaves between births, while pursuing her professional career.

Jimmie would relate how she had spent many evenings listening to her husband and his colleagues discuss the early development of chemotherapy and how it was making a real difference in pediatric acute lymphoblastic leukemia.

Those colleagues included Emil “Tom” Frei III, MD, with whom Jim Holland co-founded the Cancer and Leukemia Group B (CALGB). The two went on to share the Lasker Award in 1972 with Emil J. Freireich, MD, and Donald Pinkel, MD.

 Jimmie said:  “It was an exciting time in chemotherapy with new drugs coming down the pike, and I’d asked them if they asked their patients how they felt about their cancer, which helped develop my interest in issues relating to the psychological care and support of patients facing catastrophic diseases.”

She added, however, that in those days medical oncologists were not paying much attention to their patients’ quality of life since they were too engaged in the big problem of finding cures.

“They thought my concerns were just temporary stopgaps,” she said. “But I was around when we saw the first Hodgkin’s survivors. In the 1960s, we suddenly began to see people surviving.”

She said that she persuaded her husband who was a co-founder and then-head of CALGB to start a psychiatry committee that enabled the fledgling field of psychosocial oncology to add quality-of-life questions into larger protocols, providing more of a scientific basis to what was perceived as a “soft” science.

In addition to cancer-related social events I usually spent time with the Hollands at the American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO) annual meetings.  Jim had served as president of both organizations, and every time I saw him, his inevitable reply to my, “How are you?” was always, “Still vertical, unlike many of my colleagues.”

I will sorely miss hearing that response at AACR later this month but know that Jim and Jimmie both led long, fruitful lives that had saved the lives and soothed the psyches and emotions of countless cancer patients and their loved ones.

This article part in a series of the revival of Eric Rosenthal Reports published in Onco’Zine and formerly featured in Oncology Times.

Last Editorial Review: April 3, 2018

First published in Onco’Zine on April 3, 2018

Featured Image: Laboratory glassware containing. Courtesy: © 2010 – 2018 Fotolia.  Used with permission. Photo 1.o: In the 1950s James (Jim) F. Holland and colleagues were considered the “cowboys” of chemotherpy. Courtesy: © 2010 – 2018 National Library of Medicine | National Institute of Health.  Used with permission.

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Sanofi-Aventis In-licenses Therapeutic Antibody for the Treatment of Solid Cancers From Oxford BioTherapeutics’ – Other companies also involved in the development of ADCs

Earlier this month French pharmaceutical giant Sanofi-aventis acquired an exclusive world-wide license to one of Oxford BioTherapeutics’ internal preclinical antibody programs. Sanofi-aventis intends to use the licensed antibody, which is directed against a novel, proprietary target identified by Oxford BioTherapeutics’, to develop, manufacture and commercialize antibody-drug conjugate (also called immuno-conjugate) products for the treatment of cancer.

Under the terms of the agreement, Sanofi-Aventis agreed to pay Oxford BioTherapeutics an undisclosed upfront cash payment, milestone payments on the program, and royalties on the worldwide products sales and will receive additional performance milestones.

“This is the most advanced antibody licensing deal that OBT has signed to date and I am delighted that the target and antibody capabilities that we have built have been recognized by a world leading pharmaceutical company such as Sanofi-Aventis,” said Christian Rohlff, CEO of OBT. “Given their expertise and experience in cancer drug development, I am very pleased that a program from our broad preclinical pipeline will be developed by Sanofi-Aventis.”

The initiative integrates Oxford BioTherapeutics’ expertise in cancer target and antibody discovery with the in-house antibody development capabilities of Sanofi-Aventis. A key component of Oxford BioTherapeutics’ expertise in cancer target discovery is the company’s OGAP® proteomic database, which represents one of the world’s largest proprietary human cancer cell-surface protein repositories combined with highly relevant genomic and clinical information derived from human blood and cancer tissue studies.

Ongoing Development
Targeted cancer therapies, such as monoclonal antibodies that bind only to cancer cell-specific antigens to induce an immunological response against the target cancer cell to block the growth and spread of cancer, have become an important part of anticancer drug development. The use of monoclonal antibodies (mAbs) in an ‘unlabeled’ or ‘naked’ form as a single anticancer agent is sub-optimal. As a result, many strategies are being investigated to enhance their function. Among the options is to conjugate mAbs with radioactive isotopes, chemotherapeutic agents, or toxins to create highly targeted agents.

Antibody−drug conjugates (ADCs) are monoclonal antibodies linked to a cytotoxic small molecule. The agents combine the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules, thereby taking advantage of the best characteristics of both components and forming effective therapeutic products that attack tumor cells in a highly targeted manner.

Benefits of Antibody−drug Conjugates
Many of the new developments in anti-cancer drug development combines the long established finding of conventional cytotoxic agents and the emergence of molecularly targeted therapeutics. [1]

Anti-neoplastic drugs like doxorubicin, daunomycin, vinca-alkaloids, and taxoids, have demonstrated their ability to kill cancer cells but generally with limited selectivity and high toxic effects on normal cells yielding marginal therapeutic indices.

‘Naked’ or ‘unlabeled’ monoclonal antibodies such as rituximab, trastuzumab, cetuximab, bevacizumab, panitumumab, alemtuzumab, and ofatumumab, on the other hand, have demonstrated therapeutic utility in malignancies but are often combined with small cytotoxic drugs to achieve significant clinical efficacy.

Trastuzumab Emtansine
Trastuzumab emtansine (trastuzumab-DM1), being developed by researchers at Genentech/Roche for the treatment of HER2+ metastatic breast cancer, is a tumor-activated prodrug resulting from the conjugation of the humanized anti-HER2 mAb trastuzumab, which has been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc’s cytotoxic and antimitotic maytansine derivative DM1. [2]

Maytansinoids are potent microtubule-targeted compounds that inhibit proliferation of cells at mitosis. While antibody-maytansinoid conjugates consisting of maytansinoids (DM1 and DM4) attached to tumor-specific antibodies have shown promising clinical results, the use as single agents is limited by toxicity. Conjugating DM1 with trastuzumab results in a compound that can deliver a cytotoxic agent directly to a targeted cell while reducing most safety concerns. Preclinical studies have reported that trastuzumab emtansine potentiates the effect of a number of chemotherapeutic agents such as carboplatin, 5-fluorouracil and docetaxel, offering an exciting option for the treatment of patients with refractory, metastatic breast cancer.[3]

In ongoing phase III trial Genentech/Roche continues to evaluate Trastuzumab emtansine for 2nd-line use. The randomized trial which began in February 2009 and compares T-DM1 – used as a single agent – to lapatinib (Tykerb®) plus capecitabine (Xeloda®). Overall survival (OS) has been added as a co-primary endpoint, and the sample size increased to 980. Application for marketing approval is expected in mid-2012 in the US and Europe.[4]

Another randomized phase III trial evaluating T-DM1 for 1st-line with the goal of applying for the marketing approval of T-DM1 for this application after 2013 in the US and Europe began in July 2010 and compares T-DM1 – used as a single agent – to trastuzumab plus docetaxel or paclitaxel. [5]

Not all Approaches Succeed
Despite technological advancement, not all antibody-drug conjugates ‘winners’. Gemtuzumab Ozogamicin (Mylotarg®, Wyeth/Pfizer), a combination of the antibody gemtuzumab and the chemotherapy ozogamicin (a calicheamicin analogue), was the only U.S.-approved antibody-drug conjugate available, before the manufacturer voluntarily removed it from the market. The drug had received accelerated approval in May 2000 to treat elderly patients with acute myeloid leukemia (AML) but failed to show clinical benefit (improved survival) in a required postmarketing studie combining the agent with chemotherapy. The fatal toxicity rate was higher in patients treated with gemtuzumab ozogamicin plus chemotherapy compared to patients treated with chemotherapy alone. This raised many new safety concerns. The agent was never approved by the European Medicines Agency.

Ongoing Projects
While Genetech and ImmunoGen are developing Trastuzumab emtansine, Sanofi-Aventis [6] and ImmunoGen are collaborating on other ADCs, including SAR3419, and consisting of an anti-CD19 monoclonal antibody conjugated and the maytansinoid DM4, a derivative of the cytotoxic agent maytansine (DM1). The Anti-CD19-DM4 conjugate SAR3419 targets the cell surface antigen CD19, found on a number of B-cell-derived cancers. Upon antibody/antigen binding and internalization, the Antibody−drug conjugates releases DM4, which binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of CD19-expressing tumor cells.

In preclinical xenograft models for non–Hodgkin’s lymphoma antitumor activity of SAR3419 showed that the compound was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. As a result of this and other preclinical trials Sanofi-Aventis initiated two Phase I trials with SAR3419. One of these trials is assessing the compound when dosed every three weeks and the other one is assessing a weekly dose.[7, 8].

A multi-dose-escalation safety and pharmacokinetic study was completed in 2010. [X] These trials have yielded impressive results, particularly in the weekly dosing study. As a result, sanofi-aventis has made the decision to advance SAR3419 into Phase II after obtaining some additional information in Phase I. Phase II testing is expected to start in 2011.

Sanofi-Aventis and ImmunoGen are also working on the development SAR566658, another Antibody-drug conjugate, targeting the DS-6 epitope, which is found on breast, ovarian, cervical, pancreatic cancers and on other solid tumors. So far, preclinical results presented during the 22nd EORTC-NCI-AACR symposium on “Molecular targets and Cancer Therapeutics” in Berlin, Germany (16 – 19 November 2010) are encouraging (Abstract #ENA-0184).

More Antibody-drug conjugates
ImmunoGen’s most advanced Tumor-Activated Prodrug (TAP) compound, lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate composed of a CD56-targeting antibody with the maytansinoid DM1. Cancer that express CD56 include solid tumors, such as small-cell lung cancer (SCLC), Merkel cell carcinoma (MCC), ovarian cancer, carcinoid, and other neuroendocrine tumors. They also include multiple myeloma (MM) and certain other types of liquid cancers.

The first part of the trial, which tested different doses of the compound to establish its maximum tolerated dose, has been completed and encouraging interim data were reported at the annual ESMO meeting in October 2010. The second part of the trial is currently recruiting participants.

Exciting Progress
Positive and exciting data from a pivotal trial Brentuximab Vedotin (SGN-35) have recently been published by Seattle Genetics Inc. and Millennium: The Takeda Oncology Company Brentuximab vedotin is targeted to CD30, a defining marker of Hodgkin lymphoma, and a target also expressed on various T-cell cancers and other hematologic malignancies. It is comprised of an anti-CD30 monoclonal antibody linked to monomethyl auristatin E (MMAE). The ADC uses a novel linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. The two companies coaborating in the development and commercialization of Brentuximab Vedotin plan to submit a Biologics License Application (BLA) in the first quarter of 2011, seeking approval for both relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.

Complex Development
A number of Antibody−drug conjugates, such as trastuzumab emtansine, inotuzumab ozogamicin, and brentuximab vedotin, have reached late clinical development stages and shown encouraging therapeutic effects against both solid tumors and hematological malignancies. Today, at least fifteen promising new ADCs are being investigated in clinical trials including glembatumumab vedotin and lorvotuzumab mertansine.[Reichert]

While complex, recent encouraging successes in the development of Antibody−drug conjugate and the potential approval around the corner, are slowly leading to new ways in the treatment of a great variety of cancers, bringing hope to many patients.


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