Innovation in oncology therapeutics is advancing at a breathtaking pace. Scores of new agents and indications have been approved in the past few years by the FDA, reflecting a maturation of scientific advances that has spanned the last quarter century. Surprisingly few novel traditional chemotherapy agents have been developed during this time frame, though some derivative agents (e.g., nab-paclitaxel) have entered the standard armamentarium. An increasing number of targeted therapies are making an impact as well in this new age of precision medicine, but the most transformative advances have come from immunotherapy based on immune checkpoint antibodies.
Cancer's Primary Combatants
In 1971 the National Cancer Act was passed, marking the beginning of the war against cancer in the United States. But, in truth, we have been at war with cancer since the dawn of humanity. And, it is not an exaggeration to state that in every patient with cancer, the real war is not waged between the disease and oncologists, the medical system, or the larger society. The major conflict is between each cancer and its host immune system-the only active enemy faced by a malignancy during its development.
Abundant lines of evidence demonstrate that the immune system is not a passive entity; it struggles against developing cancers in stages that include immune editing, where immunogenic targets on tumors are whittled away, followed by an equilibrium best thought of as an uneasy truce between the tumor population and the host immune system. Eventually, the tumor may escape immune control. Hence, every successful cancer has solved the puzzle posed by the host immune system.
So, how do malignancies solve the challenge of a hostile immune system and escape immune control? Malignancies are complex ecosystems, possessing multiple clones and distinct microenvironments that make them superbly well suited to respond to any given selection pressure imposed by immune attack or any oncologist-imposed therapeutic maneuver. Cancers can overwhelm the immune response by out-proliferating it. This is likely rare, but might be seen in malignancies such as Burkitt's lymphoma.
As well, we've seen cancers hide from the immune system by down-modulating tumor antigen expression or through defective expression of MHC Class I or II molecules. We've also seen cancers subvert the immune response by expressing or inducing the expression of locally immunosuppressive chemokines or cytokines that stimulate so-called Type II immune responses that block the generation and support of CD8+ cytotoxic T cells.
Cancer can shield itself from immune attack through a variety of mechanisms that actively thwart the attraction of tumor antigen-targeted CD8+ cytotoxic T cells. And when all else fails, cancer cells defend themselves by specifically inactivating CD8+ cytotoxic T cells that have successfully navigated the tumor-protective gauntlet erected by cancer cells using immune checkpoints.
Immune Checkpoints
Immune checkpoints have been extensively described (ncbi.nlm.nih.gov/pubmed/25858804). The two prototypical checkpoints are B7: CTLA4 and PD-L1: PD1. Allison (PubMed PMID: 26359978) showed that CTLA4 is induced on CD8 T cells to compete with CD28 for binding to the B7.1 T cell co-stimulatory molecule. Unlike CD28, which activates T cells when bound by B7.1, CTLA4 emerges on T cells during the evolution of an immune response and out-competes CD28 for binding to B7.1 to inhibit T cell activation. Antibodies that block the binding of CTLA4 to B7.1 can reactivate T cells and also deplete immunosuppressive T regulatory cells.
Honjo, Freeman and colleagues originally described the PD-L1: PD1 axis about 20 years ago, and continued investigations led to an understanding of how PD1 engagement on cytotoxic T cells by tumor cell-associated PD-L1 leads to T cell exhaustion. Interestingly, PD-L1 expression on tumor cells can be induced by gamma-interferon expressed by activated, cytotoxic T cells. This elegant system of self-protection can be defeated by antibodies that block the binding of PD-L1 to PD1.
Checkpoint Antagonist Antibodies in the Clinic
Anti-CTLA4 antibody therapy has been approved for use in melanoma based upon modest overall clinical response rates, with some extremely durable responses. Other diseases demonstrate lesser rates of clinical response. Autoimmune complications can be challenging and in some cases life-threatening.
Antibodies targeting PD-L1 or PD1 have been approved for the treatment of melanoma and non-small cell lung cancer, but the spectrum of cancers that have been successfully treated with these agents is astonishingly broad. PD-L1: PD1 axis targeting antibodies have demonstrated important clinical activity in renal cell carcinoma, gastric cancer, triple-negative breast cancer, Merkel Cell tumor, bladder cancer, small cell lung cancer, malignant thymoma, and Hodgkin's disease, among others.
The list of responsive tumors is growing on a near-weekly basis. These responses have some noteworthy attributes. In most cases, a relatively small subset of each tumor type responds to antibodies directed against PD1 or PD-L1, though response rates can be quite high, as in refractory Hodgkin's disease. The trajectory of clinical response can be characterized by early pseudo-progression, and responses can slowly evolve.
Perhaps most importantly, clinical responses can be exceedingly durable. Hence, immune checkpoints seem to represent some tumors' last lines of defense against immune attack-if those checkpoints are disabled the tumors are rendered helpless.
Combinations of immune checkpoint antibodies have shown important clinical activity. Most notably, the combination of ipilumumab, an anti-CTLA4 antibody, with nivolumab, an anti-PD1 antibody, shows superior anti-tumor activity and progression-free survival in patients with metastatic melanoma as compared with either agent alone (ncbi.nlm.nih.gov/pubmed/26027431). As antibodies targeting other immune checkpoints enter the clinic and demonstrate value, many combinations will be tested, and some useful new combinations will undoubtedly emerge.
Challenges in Patient Selection
Despite the remarkable benefits of immune checkpoint inhibitor antibodies, these treatments are very expensive, can be toxic and the majority of patients treated with these agents will not benefit from therapy. These factors have inspired efforts to identify predictive biomarkers that can identify patients who are likely to benefit from therapy.
Thus far, the results are mixed. No meaningful predictive biomarkers have been validated for anti-CTLA4 therapy, and tumor cell-based PD-L1 expression is inconsistently associated with benefit from antibodies targeting PD1 or PD-L1. None of the many immunohistochemistry assays for PD-L1 expression has been validated, and the cutoffs for positivity are inconsistent. Indeed, some patients with PD-L1 negative tumors respond to inhibitor therapy. Perhaps the best indicator of potential benefit is the presence of tumor-associated, activated CD8+ T cells, though much validation work remains to be done.
A Look Ahead
In 1942, following an important Allied victory in the second battle of El Alemain, Winston Churchill famously stated, "Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning." When Rosenberg and colleagues reported the first major successes of cancer immunotherapy in 1985 it was proper to opine that perhaps this represented the end of the beginning. The battle since then has been arduous, but the data-not our hopes-show that we are witnessing the beginning of the end.
Checkpoint antibodies, alone or in combination with each other and with cytotoxic treatments, are likely to effectively treat, and possibly cure the 30 percent to 40 percent of epithelial malignancies that induce CD8+ T cell infiltration. The other cancer-protective mechanisms described above will be selectively disabled to promote T cell infiltration into tumors that can be amplified and directed by immune checkpoint antibodies. Improved biomarkers will help to choose the right treatments for patients.
These tasks will not be easy, and will not be inexpensive. The results we seek will not appear overnight. But, with persistence and patience, this approach will work.
Author's Suggested Readings
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