​Beyond immunotherapies
Forrest Anthony, MD, PhD
May 12, 2017

Oncology treatments are rapidly evolving, with the latest innovations emerging from immunotherapy research. These therapies harness the body’s own immune system to attack cancerous cells, giving new life to millions of patients. The American Society of Clinical Oncology (ASCO) named Immunotherapy 2.0 the Advance of the Year in its Annual Report on Progress against Cancer, and new therapies come to market every year promising improve quality of life, greater longevity, and in some cases full remission.

Many of the immunotherapies gaining the most attention are immune checkpoint inhibitors and diagnostic innovations, such as multiplex IHC and liquid biopsies. Cancer vaccines are also seeing a resurgence when used in combination with checkpoint inhibitors. And yet another kind of immunotherapy, genetic engineering of living immune cells and reinfusing them into cancer patients, is rapidly advancing. Experimental Chimeric Antigen Receptor T-Cell (CAR T) immunotherapyhas been astonishingly effective in certain previously terminal diagnoses. In one of the most famous examples featured in the media, Emily Whitehead, a seven year old girl with acute lymphoblastic leukemia (ALL) resistant to virtually all chemotherapies, with a terminal prognosis, achieved full remission just weeks after receiving CAR-T cells. She is completely free from cancer, and attended a recent cancer research conference in NYC with her parents, sitting in the front row. The first FDA approvals for CD-19 CAR T products are expected later this year.

However, just as much innovation is coming from molecular targeted therapies, which target specific genes or proteins in cancer cells to interfere with their growth. These treatments only work on a subset of patients with unique biologic characteristics and genetic variances, but when those genetic markers are identified the treatments can be more successful and much less toxic than chemotherapy or radiation, which were the previous standard of care. Targeted therapy is an area of oncology research that has been prominent for more than a decade, and continues to churn out new treatments to address unique tumor types across the oncology spectrum. Recently we’ve seen several advances in this space addressing a number of cancer types. Some of the most promising fall into the following categories:

  • FLT3 inhibitors for Acute Myelogenous Leukemia (AML). In about one third of patients with AML, the leukemia cells have a mutation in the FLT3 gene. FLT3 inhibitors are designed to suppress FLT3 signaling in vivo. While the first generation of these treatments failed to suppress these genes for long, second-generation FLT3 inhibitors are showing promising results. Several FLT3 inhibitors have now reached phase III clinical trials, including midostaurin from Novartis, which was granted Breakthrough Therapy designation from the US Food and Drug Administration (FDA) in 2016. There are also a variety of phase I/II trials exploring how these compounds could be used in conjunction with conventional chemotherapy or hematopoietic stem cell transplantation.
  • Antibody Drug Conjugates (ADCs): The biopharmaceutical industry has seen several promising new ADCs, which use monoclonal antibodies (mAbs) to specifically bind tumor-associated target antigens and deliver a highly potent cytotoxic agent. New combinations of mAbs have given rise to an extremely efficacious class of anti-cancer drugs, and several ADCs are currently in development, including Pfizer’s inotuzumab ozogamicin, which received priority review designation from the FDA earlier this year for patients with relapsed or refractory acute lymphoblastic leukemia (ALL), based on findings from the phase III study.
  • CD38 antibodies for the treatment of Multiple Myeloma (MM): CD38 is a surface protein that is expressed by most or all multiple myeloma cells. CD38 antibodies target and destroy these cells. They have been showing great promise in ongoing studies, spurring experts at the 56th American Society of Hematology (ASH) Annual Meeting to predict they will become the next blockbuster drug for this malignancy.
  • In 2015, Janssen Biotech daratumumab became the first human anti-CD38 mAb approved for patients with multiple myeloma in combination with a number of drugs representing the standard of care. Morphosys and SanofiAventis also have CD38‐specific antibodies in clinical development. It is believed that CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody‐mediated autoimmune diseases.
  • Cyclin-dependent kinases (CDK) 4/6 for estrogen-receptor-positive breast cancer: CDK 4/6 are a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin dependent kinase 4 and 6. Pfizer’s palbociclib was the first CDK 4/6 inhibitor to win accelerated approval in February 2015, and regular approval in 2017. Several others, including Eli Lilly’s abemaciclib and Novartis’ ribociclib are in late stages of development.

The ASCO report also notes recent discovery of genes linked to ovarian cancer risk (RAD51C and RAD51D0), new pancreatic cancer susceptibility genes (CDKN2A, BRCA1/2, PALB2), and the discovery that many cases of pediatric cancer are associated with hereditary gene mutations predisposing these children, may lead to new kinds of targeted therapies.

Beyond targeted therapies, there also have been recent advances in the “older” area of chemotherapy, including new combined modality therapies being used to improve the chance of cure or decrease the risk of complications through the use of multiple treatments. For example, in 2016, it was found that combining the two chemotherapy drugs capecitabine and gemcitabine prolongs survival in patients with pancreatic cancer without increased toxicity. As we learn more about chemotherapy, and how it functions in combination with other treatments, we can expect new applications in cancer therapy.

All these advances are evidence of an accelerating pace of scientific discovery, investments, clinical trial activity, and approvals in the rapidly growing oncology field. Targeted therapies have transformed the once broad category of cancer patients into a field of rare diseases, each of which can be addressed by targeting therapies to specific genes. These therapies may not be as sexy as some of the newer immunotherapies coming to market, but for patients with once untreatable forms of cancer, they offer hope and promising lifeline for the future, and may combine well with the new immunotherapies.

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