Therapeutic Antibody conjugates proven clinically effective with acceptable toxicity

Antibody Drug Conjugates (ADCs) have shown a clearly documented efficacy and acceptable toxicity and can be easily implemented in oncology departments where chemotherapy administration is a routine practice. A similar efficacy with acceptable toxicity has been documented with Antibody Radionuclide Conjugates (ARCs) which need to be injected with the help of a nuclear medicine department which can be a limitation for referral from an oncologist.

In a review collecting the clinical results of 11 studies including 598 patients treated with 6 Antibody Drug Conjugates and 9 studies (including 377 patients treated with 5 Antibody Radionuclide Conjugates), toxicity was generally less frequent with Antibody Drug Conjugates than with Antibody Radionuclide Conjugates but often led to more uncomfortable side effects. Both conjugates have shown some clinical efficacy in terms of survival (progression free survival or overall survival) depending on the tumor type, radiosensitive or not.

The good results of both conjugates could be significantly improved in the future. Targeting Cancer Stem Cells (CSC) using both cytotoxic payloads (drugs or radionuclides) could delay tumor relapse. Preclinical studies have shown a promising therapeutic index with long-term tumor regression warranting a clinical application.

Efficacy of Antibody Radionuclide Conjugates could be improved with the use of alpha-emitting radionuclides which deliver a high fraction of their energy inside the targeted tumor cell leading to highly efficient killing especially for isolated tumor cells or clusters of malignant cells in the body.

The efficacy of both Antibody Drug Conjugates and Antibody Radionuclide Conjugates could be enhanced by parallel treatment with immune checkpoint inhibitors thus providing synergistic immunogenic cell death.

In conclusion therapeutic immunoconjugates using chemotherapeutic drug or radionuclides as cytotoxic payloads have clearly shown clinical efficacy, which could be significantly improved in the near future.

Citation: Chatal, Jean-François, Françoise Kraeber-Bodéré, Caroline Bodet-Milin, and Caroline Rousseau. “Therapeutic Immunoconjugates. Which Cytotoxic Payload: Chemotherapeutic Drug (ADC) or Radionuclide (ARC)?.” Current Cancer Therapy Reviews 12, no. 1 (2016): 54-65.
DOI: http://dx.doi.org/10.2174/1573394712666160805121312
Adapted from press release by Bentham Science Publishers.

Research shows tumor-targeted radiosensitization using antibody drug conjugates may redues toxicity and improve outcome

Many types of cancer become drug resistant, making them difficult to treat. Researchers with University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to selectively sensitize certain cancer cells to radiation therapy that may improve tumor control and reduce treatment-related side effects.

In a paper published in Nature Communications, researchers report that in mouse models tumors testing positive for a protein called human epidermal growth factor receptor 2 (HER2) were sensitized to a combination of radiation therapy and an antibody drug conjugate (ADC) called ado-trastuzumab emtansine (T-DM1). ADC is a new technology that chemically links an antibody to a targeted cell receptor to deliver a drug to specific cells — in this case a very potent chemotherapy to HER2 positive tumors — while sparing normal tissue.

“A biomarker-driven, tumor-targeted radiosensitization approach to treating cancer is a potentially significant advancement from current chemotherapy and radiation therapy,” said Sunil J. Advani, MD, associate professor in the Department of Radiation Medicine and Applied Sciences and the paper’s senior author. “Non-targeted, highly toxic chemotherapies continue to remain the most effective treatments for patients treated concurrently with chemotherapy and radiation, but these treatments have significant toxicity and we need alternatives that are molecularly guided based on mutations found in specific patients.

The study shows promise in HER2 cancers, which occur in a percentage of lung, esophageal, gastric and bladder cancers. T-DM1 is already approved for use in metastatic HER2 positive breast cancer treatment. Researchers repurposed the existing drug to sensitize cancer cells to radiation therapy among patients who simultaneously receive chemotherapy and radiation therapy at the beginning of the treatment process, instead of waiting until the cancer spreads or becomes resistant to treatment.

Intensifying a dose of non-targeted chemotherapies increases normal tissue toxicities, often precluding further radiation therapy or chemotherapy escalation. Using targeted ADC with radiation therapy would reduce toxicity, reduce the risk of tumor resistance and attacks both known tumors as well as cancer cells that may have metastasized, while sparing normal tissue.

Type of study: Mouse model
Publication: Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize
doi:10.1038/ncomms13019
Antibody drug conjugates may help personalize radiotherapy for patients with cancer