July 2012 Edition Vol.6, Issue 4

The Promising Outlook With Immunoconjugate Therapy

The Promising Outlook With Immunoconjugate Therapy

By Mark Green, MD & Loreen Brown, MSW

The search for a “perfect” or even “nearly perfect” cancer therapy—one which can identify and kill tumor cells wherever they reside in the host without injuring normal tissues—remains a Sisyphusian task.1 Joining the ranks of combating this task are the development of immunotherapies—treatments that use the body’s own immune system to fight cancer and one that holds great promise for delivering effectiveness with minimal toxicity. Very recently, for example, the anti-CTLA4 antibody, ipilimumab, was approved as a first-line or salvage management for patients with advanced malignant melanoma.

In an advanced disease population, the median overall survival with ipilimumab alone was 10.1 months compared with 6.4 months for a proprietary vaccine alone (hazard ratio [HR] 0.66; P=0.003). However, toxicity was not insignificant. Seven patients experienced on-study deaths related to immune adverse events.2 Moreover, unique response patterns and toxicities associated with ipilimumab therapy led to the development of a new set of immunotherapy-related response and toxicity criteria.3

Alternatively, immunoconjugates represent a matrix of emerging science, including monoclonal antibody targeting of tumor cells and effective linkage of highly toxic therapeutic moieties to the targeting antibody in protected “pro-drug” configurations. This allows systemic trafficking, delivery, internalization, intracellular decoupling of the toxic therapeutic package from the delivery vehicle, and retention of the cytotoxic moiety within the tumor cell target. The conjugated killing agent can be a traditional chemotherapeutic cytotoxic, a natural toxin, or a radiotherapeutic agent. Off-target toxicity is reduced as minimal systemic exposure to the active cytotoxin occurs.

Several immunoconjugates have been approved for treatment in selected hematologic malignancies. Gemtuzumab ozogamicin, in which calicheamicin, a natural enediyne antibiotic, is linked to an anti-CD33 antibody, was accorded accelerated approval in May 2000, with the target disease of acute myeloid leukemia.4 However, the agent was voluntarily withdrawn by its manufacturer in 2011 when Phase 3 data failed to confirm the survival benefit suggested by the Phase 2 data that had led to its initial FDA accelerated approval.4 Another calicheamicin immunoconjugate, inotuzumab ozogamicin, has an anti-CD22 targeting antibody and is currently in Phase 3 testing in selected B-cell neoplasms.5

Last year, brentuximab vedotin, in which an anti-CD30 antibody is linked to the potentially highly toxic antitubulin agent monomethyl auristatin E (MMAE), was approved for patients with relapsed Hodgkin’s disease or anaplastic large cell lymphoma, both of which express CD30. The activity of brentuximab vedotin among patients with advanced, previously treated disease is impressive.6 However, systemic immune suppression has led to an increased risk of progressive multifocal leukoencephalopathy (PML) associated with brentuximab vedotin therapy.7 Other similar agents are currently in development.8

The first immunotoxin conjugate approved for cancer therapy was denileukin diftitox, a recombinant protein with critical components of both human interleukin-2 (IL-2) and truncated diphtheria toxin. The engineered protein binds to the IL-2 receptor and delivers the diphtheria toxin.9 This agent was given accelerated FDA approval in 1999 and received full approval in 2008 for use in patients with progressive CD25-positive cutaneous T-cell lymphoma.10 Usage has been limited, however, and other agents dominate cutaneous T-cell lymphoma therapy.

For patients with relapsed/refractory hairy cell leukemia, a new immunotoxin, moxetumomab pasudotox, has been recently reported to produce an 86% response rate, including 46% complete responses (CRs) in 26 evaluable patients. Only one of the 13 patients who reached CR has had disease recurrence within the first year of therapy.11

In follicular lymphoma, two radioimmunotherapeutics, Yttrium-90 ibritumomab tiuxetan12 and Iodine-131 tositumomab13 are FDA approved as single-agent therapies. Despite high levels of single-agent activity and important improvements in progression-free survival when used following induction chemotherapy, overall utilization is low for a variety of reasons, including reimbursement hurdles.

The Success of T-DM1 Activity

At ASCO this year, a new immunoconjugate entrant, focused on a common solid tumor, had its Phase 3 coming out party, and it was a wow!14 The agent is trastuzumab emtansine (T-DM1), an immunoconjugate that combines the anti-HER2 antibody trastuzumab (T) with the antitubulin chemotherapeutic agent mertansine (DM-1), a derivative of the maytansine. Trastuzumab is a widely utilized anti-HER2 antibody with substantial single-agent activity in patients with HER2-positive breast cancer and HER2-positive gastric carcinoma. The development of trastuzumab ushered in a new paradigm in solid tumor therapy. Yet despite the enrichment driven by HER2 status, objective response rates with trastuzumab as a single agent for patients with metastatic breast cancer (mBC) settle in the 20%–35% range.15

When added to chemotherapy as first-line management for patients with HER2-positive mBC, response rates are high and survival is statistically significantly improved vs chemotherapy alone.16 As a part of adjuvant therapy in patients with completely resected HER2-positive breast cancer, the reduction in risk of disease recurrence contributed by trastuzumab therapy is nearly 50%.17 Even with its single-agent potential for cardiac toxicity, which is heightened further when integrated or sequenced with anthracycline therapy, the clinical impact of trastuzumab in patients with breast cancer is enormous. T-DM1 appears to retain the actions of trastuzumab as a single agent while also delivering the intracellular toxin mertansine specifically to breast cancer cells.

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