Back in Blog #9, I promised to return to this (yet another) complex topic, but I also promised to be brief. So, once again, let me take a quick shot at making this particular aspect of cancer therapies “as simple as possible, but…" Yeah, yeah, you know.”
Cancer immunotherapy, also known as immuno-oncology, is a form of cancer treatment that uses the power of the immune system to treat and hopefully, eliminate cancer. There are numerous forms of immuno-oncology, many of which we have discussed above including targeted antibodies, cancer vaccines, adoptive cell transfer, checkpoint inhibitors, cytokines, biologics, gene therapies, and adjuvants (treatments given in addition to the initial treatment, e.g., surgery, chemotherapy, radiation, or targeted therapies). Combinations of these types of therapies, particularly with certain monoclonal antibodies effecting targeted immune checkpoints, have shown considerable promise in cancer therapies.
A research scientist with the MD Anderson Institute, Jim Allison, Ph.D., yet another immunology Nobel Laureate (2018), invented immune checkpoint blockade immunotherapy which blocks the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on T cytotoxic cells (another cell first introduced in Blog #5), freeing these killer immune cells to attack cancers. Blocking the CTLA-4 also liberates T cells to assume new identities, including one that is vital to an effective response against tumors. CTLA-4 and programmed cell death protein 1 (PD-1 – descripted in Blog #21 and 29), both inhibitory checkpoints commonly seen on activated T-cells, have been found to be the most reliable targets for the treatment of cancer. Six drugs targeting PD-1 or its ligand PD-L1 (on the cancer cell) in combination with another drug targeting CTLA-4 (Nivolumab [Opdivo]) have been approved for treatment of different types of cancers and several others are in advanced stages of development.
The drugs, when administered as monotherapies, showed dramatic increase in their durable response rates and had manageable safety profiles for patients, but more than 50% of patients failed to respond to treatment. A combination of CTLA-4 and PD-1 blockers was evaluated to increase the response rates in patients, ipilimumab (Yervoy, an anti-CTLA-4) plus nivolumab (Nivolumab [Opdivo], an anti-PD-1). In combination they showed to significantly enhance efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma, and metastatic colorectal cancer. The success of such “combination strategies” has encouraged multiple clinical studies in other cancer types. The efficacy of combinations has been shown in a number of published studies and more combination therapies are under evaluation in multiple ongoing studies. They will include surgery; chemotherapies; radiation therapies (X-rays and proton beam); “molecular target therapies”; biologic agents; hormones; signal transduction inhibitors; gene expression modulators; apoptosis inducers; angiogenesis inhibitors; “small-molecule drugs”; checkpoint inhibitors; and monoclonal antibodies; as well as genetic engineering (editing and replacement therapies); and stem cell therapy. Clearly, combination therapies guided by artificial intelligence will play a significant role in future treatment of cancers.
Discussion Questions:
CTLA-4 and programmed cell death protein 1, both inhibitory checkpoints commonly seen on activated T-cells, have been found to be the most reliable targets for the treatment of cancer. Can you name some (or any) of the FDA-approved drugs (6) targeting PD-1 or its ligand PD-L1?
Ipilimumab (Yervoy, an anti-CTLA-4) plus nivolumab (Nivolumab [Opdivo], an anti-PD-1) in combination showed significantly enhance efficacy in what form of metastatic cancer?
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