By Christopher R. McCurdy, Ph.D., FAAPS, President
This is an exciting time in cancer research. Breakthroughs in immunotherapies offer new promise to patients. Immuno-oncology covers many different ways to use the immune system to kill cancer cells. To present a comprehensive view of breakthroughs in immuno-oncology, the AAPS PharmSci 360 Scientific Programming Committee chose immuno-oncology as one of its two end-to-end hot topics. Symposia will follow the topic through the entire drug development process in each of five meeting tracks:
- Preclinical development
- Bioanalytics
- Formulation and quality
- Manufacturing and bioprocessing
- Clinical pharmacology
Immuno-oncology stimulates our immune system to recognize and fight cancer cells or give us immune-system components, such as man-made proteins or antibodies, that help the immune system fight cancer cells.
News reports broadcast advances in cancer research, and one of the more recent breakthroughs is chimeric antigen receptors (CARs). This technique removes T cells from the patient’s blood and genetically alters them to have specific antigen receptors on their surface, which in turn will attach to proteins on the surface of cancer cells. After several weeks of creating CAR T-cells, they are infused back to the patient to precisely attack the cancer cells. The Food and Drug Administration (FDA) has approved the first CAR-T therapies: Kymriah for advanced leukemia and for large B-cell lymphoma, Yescarta for large B-cell lymphoma.
Monoclonal antibodies (mAbs) have played a large role in fighting cancer, and FDA has approved more than a dozen of them as cancer therapeutics. MAbs like Campath attach to cancer cells and act as a marker for the immune system to destroy them. Others, like Herceptin, attach to and block antigens on cancer cells.
Conjugated mAbs join with a chemotherapy drug (chemolabeled) or radioactive particle (radiolabeled) to find and hook onto the target antigen and deliver the toxic substance where it is needed most, lessening damage to normal cells.
Bispecific mAbs comprise parts of two different mAbs so they can attach to two different proteins simultaneously. For the drug Blincyto, used to treat some types of acute lymphocytic leukemia, one part attaches to the CD19 protein found on some leukemia and lymphoma cells, and another part to the CD3 protein found on T cells, thus bringing a target antigen and an activating receptor on the surface of an immune effector cell together, opening an opportunity for the T cells to kill cancer cells.
Work on antibody-cytokine fusion proteins focuses on harnessing the tumor -targeting ability of monoclonal antibodies. Guiding cytokines to tumor sites directs the antitumor immune response to narrow impact on the rest of the body. Interleukin-2 has encountered some success, as have the interferons. Therapeutic antibodies that can bind specifically to tumor -associated cell surface antigens or other targets within the tumor microenvironment can be engineered to transport cytotoxic agents, radioisotopes, or other payloads such as cytokines directly to tumor sites. Using recombinant DNA techniques, genes encoding cytokines can be joined to antibody genes to create antibody-cytokine fusion proteins.1
Similarly, antibody-drug conjugates (ADCs) offer selective delivery of cytotoxic agents to tumor cells. Using mAbs specific to tumor cell-surface proteins provides tumor specificity and potency not available with drugs alone.2 Adcetris is an ADC that targets CD20 found in Hodgkin lymphoma and several types of non-Hodgkin lymphoma comprising an anti-CD30 mAb, monomethyl-auristatin E microtubule-disrupting agent, and a protease-cleavable linker. Kadcyla is an HER2-targeted ADC comprising the mAb, the cytotoxic maytansinoid, and a stable linker.
Using retroviral vectors to retarget immune cells to recognize and eliminate tumor cells is an emerging therapeutic strategy. They are instrumental in producing CAR-T cells. Retroviral delivery of clustered regularly interspaced short palindromic repeats associated nucleases, zinc-finger nucleases, or TAL -effector nucleases has the potential to specifically delete oncogenes, inactivate oncogenic signaling pathways, or deliver wild-type genes. The possibility exists for retroviral gene transfer strategies to protect the hematopoietic stem cells from the dose-limiting toxic effects of chemotherapy and radiotherapy.3
Immune checkpoint inhibitors target checkpoints used by cancer cells to avoid attack by the immune system. Checkpoint protein PD-1 keeps T cells from attacking normal cells when it attaches to PD-L1. Because some cancer cells have large amounts of PD-L1, they can evade immune attack. MAbs that target PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells. PD-1 inhibitors include recently approved Keytruda and Opdivo.
Cancer vaccines are not yet a major treatment for cancer, but research continues. For tumor cell vaccines, cancer cells are removed from the patient, altered and killed in the lab to increase the likelihood they will be attacked by the immune system, and then injected back into the patient. The immune system attacks these and similar cells in the body. Antigen vaccines use proteins or peptides to boost the immune system against a specific type of cancer. Dendritic cell vaccines have shown the most promise against cancer cells. Immune cells are taken from the patient’s blood, exposed to cancer cells or antigens, and injected back into the patient. Vector -based vaccines can deliver more than one cancer antigen at a time.
Symposia in the AAPS PharmSci 360 immuno-oncology end-to-end topic include the following:
- Immuno-Oncology: What, Why, and When?
- Fighting Cancers with Oncolytic Viruses: Bioanalytical Considerations
- Immune Checkpoint Inhibitors: Clinical Pharmacology Considerations
- Advances in the Manufacture of Large DNA Viruses for Use as Oncolytic Therapies
- Emerging Modalities for Cancer Therapeutics
See what else this new AAPS meeting in November has to offer on the PharmSci 360 website.
REFERENCES
- Young PA, Morrison SL, Timmerman JM. Antibody-Cytokine Fusion Proteins for Treatment of Cancer: Engineering Cytokines for Improved Efficacy and Safety. Semin Oncol. 2014;41(5):623–636. doi:10.1053%2Fj.seminon col.2014.08.002
- Lambert JM, Berkenblit A. Antibody-Drug Conjugates for Cancer Treatment. Annu Rev Med. 69:191–207. doi:10.1146/annurev-med-061516-121357
- Schambach A, Morgan M. Retroviral Vectors for Cancer Gene Therapy. In: Walther W, ed. Current Strategies in Cancer Gene Therapy. Recent Results in Cancer Research, volume 209. Switzerland: Springer; 2016:17–25. doi:10.1007/978-3-319-42934-2_2