Dr. Drew M. Pardoll, Johns Hopkins University School of Medicine in Baltimore, in his 2012 review, “The blockade of immune checkpoints in cancer immunotherapy” published in Nature Reviews Cancer (1) writes:
“The myriad of genetic and epigenetic alterations that are characteristic of all cancers provide a diverse set of antigens that the immune system can use to distinguish tumour cells from their normal counterparts.”
Tumors have antigens, so we should be able to address/attack these antigens with our immune system, right?
Various immune mediators as therapeutic agents against cancer have entered and mostly flopped in clinical trials over the past 30 or more years. As a graduate student in the 1980s I remember IL-2 and interferon raising many hopes. More recently, drugs against chronic myeloid leukemia and CLL have shown early promise. However, so far cancer cells have mostly won against these therapies. Yet recent news points to some exciting new therapeutic agents, that over the past 15 years or so, and in and out of clinical trials, are getting a leg up in the cancer battle. These drugs are immune checkpoint inhibitors.
What are Immune Checkpoint Inhibitors?
Our immune system operates to keep us healthy by eliminating invading pathogens. Pathogens are recognized as foreign due to antigens, proteins on their surface that interact with our immune system. The antigens are brought into contact with receptors on the surface of T cells, which initiates a cascade of cellular and chemical activities, all designed to kill and remove the pathogen. Over the course of hours and days, the size or amplitude of this immune response continues to increase, resulting in a huge influx of various cells, including helper, killer and regulatory T cells.
Moreover, the immune response result in a release of chemicals that help to destroy and remove the foreign agent. These chemicals could potentially accumulate and damage our healthy cells. If you’ve ever had a reaction to an antibiotic, or a bee sting, you know how severe unchecked immune response can be. In the event of a bee sting or a reaction to antibiotics, your doctor might prescribe drugs to shut down this unchecked immune response and avoid tissue damage.
The immune system in all of its elegance and ferocity has checkpoints that provide a feedback mechanism to keep the response from going too far.
And cancer cells, with possibly greater ferocity, have evolved the ability to use immune checkpoints to evade immune response. The latest in cancer therapies revolves around blocking the checkpoints, that is, developing immune checkpoint inhibitors, to attack cancer.
Checkmate? Let’s take a look.
CTLA4 is an immune checkpoint regulator and the first one for which a clinical therapy was developed. It is found exclusively on T cells and is responsible for modulating the size of the T cell response in its early stages.
The role of CTLA4 as an immune system checkpoint regulator has been demonstrated in CTLA4 receptors knockout mice. These mice suffer a lethal systemic immune hyperactivation event when an immune response is needed; the CTLA4 checkpoint is apparently crucial for survival (1).
In his review on check point inhibitors, Pardoll notes that the major physiological role of CTLA4 seems to be down modulation of T helper cell activity, while enhancing T regulatory cell activity. Blocking CTLA4 activity results in enhanced CD4+ T helper cells, and suppression of regulatory T cells (1).
Fast forward to CTLA4 in Cancer Therapy
Several CTLA4 antibodies were investigated starting in 2000; one of these became the first therapeutic antibody to show a survival benefit in patients with metastatic melanoma and thus was approved by the FDA in 2010. This drug, ipilimumab, showed impressive long-term survival, with nearly 20% of patients surviving >2 years, notable in particular because the treatment time course was relatively short. In fact, on-going survival data seems to demonstrate that anti-CTLA4 antibodies continue to work well past their last administration and may in fact be re-educating the immune system to keep tumors in check past therapy administration (1).
Anti-CTLA4 clinical responses have been shown to have unique kinetics compared to conventional chemotherapeutic agents. In some patients, response to immune checkpoint inhibitors was not seen for as long as 6 months after initiation of treatment, compared with responses within weeks to chemotherapy and tyrosine kinase inhibitors. In a number of cases, metastatic lesions appeared to increase in size when viewed on CT scans, before regressing and disappearing.
It Gets Better: About PD-1
Pardoll notes that another immune checkpoint inhibitor, PD-1, is showing even more exciting results. PD-1 is short for programmed cell death protein 1, and its main role as a checkpoint inhibitor is to limit T cell activity in peripheral tissues during inflammatory events. This distinguishes
PD-1 from CTLA4, because PD-1 can be found inside the tumor microenvironment. Activated T cells stimulate PD-1 expression, which then acts to inhibit kinases involved in further T cell activation (1).
Like CTLA4, PD-1 is highly expressed on regulatory T cells and because tumors are highly infiltrated with these regulatory T cells, which can act to block immune responses, blocking the PD-1 receptor may diminish the suppressive activity of regulatory T cells in the tumor.
The difference between CLTA4 and PD-1 is that PD-1 primarily regulates effector T cell activity in the tumor environment, while CTLA4 primarily regulates T cell activation. PD-1 is more broadly expressed and is upregulated on other non-T cells, including B cells and natural killer (NK) cells, limiting their lytic activity.
PD-1 is expressed on the surface of many tumor infiltrating lymphocytes, and PD ligands (PDL1 and PDL2) are commonly found on the surface of tumor cells from many different human cancers. Researchers have found that forced expression of PDL1 on mouse tumor cells inhibits local antitumor T cell-mediated responses (1). PDL1 was initially reported to be highly expressed on the surface of most melanoma, ovarian and lung cancer samples; additional other human cancers have now been added to the list as showing high expression of PD-1 (1).
Mouse models of cancer have demonstrated enhanced antitumor immunity via blocking of PD-1 or its ligands. In addition, knockout mice missing PD-1 ligands PDL1 or PDL2 demonstrated a potential for less toxicity, than for the CLTA4 blockade. Clinical trial results appear to bear this out, with lower toxicity of PD-1 relative to CTLA4 therapy (1).
Clinical experiences with PD-1 antibodies in humans have shown promising tumor regressions in 4 of 5 histological samples of renal, melanoma, colon and lung cancers. In a trial extending more than 2 years, 16 of 39 patients with advanced melanoma showed objective responses.
On its web site the MD Anderson Cancer Center posted this August 2014 article including a cancer checkpoint survival story, “Immune Checkpoint Inhibitors Show Promise Against Metastatic Renal Cell Carcinoma, Other Difficult-to-Treat Cancers” that provides some recent and encouraging real-life results on the use of immune (cancer) checkpoint inhibitor therapy.
Immune checkpoints are about to hit the big screen as well. Ken Burns and Barak Goodman are releasing, on PBS at the end of March 2015, a film based on the 2011 Pulitzer Prize winning book, “The Emporer of All Maladies”, by Siddhartha Mukerjee. Here you can watch a trailer for the film .
It is such a very exciting and hopeful time for cancer patients, cancer researchers and oncologists. One would be remiss to not note, the many patients that have participated in clinical trials, successfully and otherwise, and the many researchers who have devoted their careers to finding these answers and continuing the struggle against cancer. We owe them all a very large debt of gratitude.
- Pardoll, D. M. (2012) The blockade of immune checkpoints in cancer immunotherapy . Nature Reviews/Cancer 12, 252–64.
More information on PD1 and PDL1:
Guha, M. (18 Nov 2014) “The New Era of Immune Checkpoint Inhibitors” The Pharmaceutical Journal.