In 2013, Science ranked cancer immunotherapy as "the most significant breakthrough of the year".Cancer treatment has ushered in changes, from the previous focus on the tumor cells themselves, to now open new therapies for the immune system, cancer treatment ideas have changed dramatically.
In 2018, the Nobel Prize in Physiology or Medicine was awarded to two researchers, respectively: Dr. Tasuku Honjo, Kyoto University, Japan, and Dr. James Allison, Anderson Cancer Center.
Recently, the top international medical journal JAMA reviewed the achievements and perplexities we have achieved in cancer immunotherapy in the past few years, and looked forward to possible future research directions.With author M.J.In Friedrich's words, immunotherapy has entered 2.Time 0.
1, immunotherapy 2.Time 0: Success & Difficulty
The awards of Dr. Tasuku Honjo and Dr. James Allison of the Anderson Cancer Center at Kyoto University in Japan stem from the discovery of two immune checkpoint pathways that inhibit CD8 + T cells and prevent them from destroying cancer cells.
In the mid-1990s, Allison demonstrated that blocking CTLA-4 protein (cytotoxic T-lymphocyte protein 4) can shrink tumors in mice.Around the same time, Honjo discovered a second immune checkpoint pathway, the PD-1 (programmed cell death protein) pathway.Activated T cells contain PD-1 protein on their surface.Cancer cells bind to the PD-1 protein with their own surface ligands, resulting in inhibition of T cell activity.
These immune checkpoint pathways were originally designed to prevent T cells from attacking healthy tissues, but were exploited by tumor cells to evade the encirclement of T cells.These studies prompted scientists to begin the development of immune checkpoint inhibitors.
Existing immune checkpoint inhibitors include anti-PD-1 monoclonal antibody, anti-PD-L1 monoclonal antibody, and anti-CTLA-4 monoclonal antibody.
Representative anti-PD-1 mAbs include pembrolizumab and nivolumab.Both bind to the PD-1 protein on T cells and prevent it from binding to the ligand protein PD-L1 (programmed cell death ligand) on the surface of cancer cells, thereby exposing the cancer cells to the view of the immune system.Other checkpoint inhibitors, such as atezolizumab, achieve the same effect by targeting PD-L1, a ligand on the surface of cancer cells.CTLA-4 antibodies, including ipilimumab, work in a manner similar to anti-PD-1/PD-L1.Activation of T cells depends on dual activation of the first signal (antigen/antibody complex formation) and the second signal (B7-mediated activation signal), whereas binding of CTLA4 to B7 inhibits T cell activation.Ipilimumab, a targeted immunotherapy drug, can just block the binding of CT-LA4 to B7, remove immunosuppression and mobilize specific anti-tumor immune responses.These immune checkpoint inhibitors, as well as several others, are now approved by the US FDA.
Despite the great potential of these immune checkpoint inhibitors, it is currently only possible to act on certain specific types of cancer, such as melanoma, lung, renal cell, and bladder cancers, as well as cancers with microsatellite instability with high mutational load.Even in these tumor types, not all tumors respond to checkpoint inhibitors.
Therefore, there are two major difficulties facing researchers: 1) how to use it to maximize the efficacy of immune checkpoint inhibitors and minimize toxicity; 2) how to expand the use of immune checkpoint inhibitors to a wider range of cancer types.
2, Biomarkers used to predict efficacy: CD8 + T cell infiltration and tumor mutation burden
There are currently nearly 2,000 clinical trials of immune checkpoint inhibitors for single and combination therapies.
To enhance the efficacy of immunotherapy, many trials have combined immune checkpoint inhibitors of CTLA-4 and PD-1/PD-L1.Although this combination therapy is usually more effective than monotherapy, the risk of adverse events should not be underestimated.There is an urgent need for reliable biomarkers in the medical community to screen out patients suitable for single and combination therapies.
Dr. Padmanee Sharma of the Anderson Cancer Center and her husband Allison worked on developing and improving checkpoint inhibitors for many years.She is conducting a new study to assess whether CD8 + T cell infiltration in tumors can be used as a biomarker to predict the efficacy of immune checkpoint inhibitors.
The premise of this study is that "hot" tumors with high CD8 + T cell infiltration will respond to a PD-1 inhibitor such as nivolumab, whereas "cold" tumors with low levels of CD8 + T cells may require additional help with CTLA-4 inhibitors to allow T cells to enter the tumor.Based on this premise, Dr. Sharma divided the volunteers into two groups using nivolumab monotherapy or nivolumab and ipilimumab combination therapy, and the grouping principle depended on whether the CD8 + T cell infiltration was high or low in the volunteers' tumors.
All types of patients with advanced metastatic cancer are involved in clinical trials.Sharma and colleagues hypothesized that a proportion of all solid tumors (even those considered "cold" like pancreas and prostate cancer) may have the properties of high CD8 + T cells, which may make them responsive to checkpoint blockade.
Another biomarker currently evaluated by the FDA is tumor mutation burden (TMB).Dr. Matthew Hellmann, who commemorates the Sloan Kettering Cancer Center, said that every mutation in the tumor has the potential to produce "new antigens" that can act as "warning lights" for the immune system to alert it to cancer cell invasion.
A few years ago, Hellmann and colleagues demonstrated that treatment with pembrolizumab works well in NSCLC patients with higher TMB.Hellmann said, "Since then, a positive correlation between high TMB and immune checkpoint inhibitor response has been found in most cancer types studied.A prime example of this situation can be found in patients with genetic disease caused by a deficiency of mismatch repair genes, which can also lead to the development of tumors with high microsatellite instability.In 2017, pembrolizumab received FDA approval for high microsatellite instability tumors, regardless of where the cancer originated.This is the first FDA approval based on a biomarker rather than a single tumor indication.
However, no biomarker is perfect.For example, four different immunohistochemical tests for detecting high PD-L1 tumor expression have received FDA approval for certain cancer indications (including non-small cell lung cancer), but PD-L1 expression does not always accurately predict which patients will or will not respond to immune checkpoint inhibitors.
Hellmann states, "Taken together, various biomarkers may predict efficacy from different perspectives."
3, gut microbiota as biomarkers and modulators
According to several recent studies by Houston, Chicago and French researchers, the diversity and composition of the gut microbiome is another factor influencing the response to immune checkpoint inhibitors.Researchers are now beginning to investigate the use of gut microbes as biomarkers and modulators of the checkpoint blockade response.
Dr. Jennifer Wargo at Anderson Cancer Center will collaborate with the Parker Institute and Seres Therapeutics to conduct phase I clinical trials to explore both possibilities.The study will randomize patients with metastatic melanoma to use 1 of 3 therapies before starting anti-PD-1 therapy: oral tablets containing fecal microbiota from anti-PD-1 responders; oral tablets containing a specific mixture of microorganisms (mimicking the microbial components found in anti-PD-1 responders) or placebo.
In another phase II trial, Dr. Hassane Zarour of the University of Pittsburgh is investigating whether fecal microbiota transplantation in long-term anti-PD-1 responders can improve the efficacy of PD-1 inhibitors in patients with resistant PD-1 melanoma.
Similar to the Wargo research team, the aim of the study by Zarour and coworkers was also to determine which specific microbiota could modulate the response to immune checkpoint inhibitors.
4, breaking the "ceiling" that limits efficacy
Dr. James Gulley, Director, Division of Urogenital Malignancies, NCI, Bethesda, said, "Responding to immune checkpoint inhibitors requires T cells to enter the tumor microenvironment.If T cells are no longer in the tumor microenvironment, they must be placed in the tumor microenvironment anyway."Many tumors escape T cell infiltration, and scientists are exploring ways to solve this problem.A molecular marker that prevents T cells from entering the tumor microenvironment is transforming growth factor beta (TGF-β), a cytokine that has many functions, including immunosuppression.To overcome this obstacle, Gulley has been working on M7824.M7824 is an enhanced version of PD-L1 that can antagonize both TGF-β and PD-L1, and both systems have a synergistic effect at the same time.
Gulley and his team have started phase I and II trials of M7824 for patients with metastatic castration-resistant prostate cancer, a cold tumor.This novel experimental design accelerates the evaluation of four different experimental reagents targeting five different immune targets.Gulley said, "If we study each drug separately in a subsequent phase II study, it will take a long time."
In this trial, the Gulley R & D team set up three study groups, the enrollment of the three study groups will be sequentially advanced, and after the safety of the drug combination used in the previous study group is confirmed, a new immunotherapy formulation will be subsequently added by one of the study groups.All patients were treated with M7824.
"This is an adaptive trial design, and we keep advancing, adding another drug until we get a clear clinical signal," Gulley said.
Another innovative approach is to use CD40 antibody therapy to prime the immune system and sensitize tumors to immune checkpoint inhibitors.Dr. Robert Vonderheide, director of the Alberramson Cancer Center at the University of Pennsylvania, said that his laboratory data show that CD40 can be used as a "converter" to convert cold tumors that do not produce enough immune responses into hot tumors that can produce immune responses.The CD40 antibody is the agonist that turns this switch on.In addition, there are experimental data from other scientists to support this.
Vonderheide is collaborating with the Parker Institute in Phase Ib and Phase II clinical trials to investigate whether anti-CD40 antibodies can improve immune checkpoint blockade in patients with pancreatic cancer.Pancreatic cancer is the least "cold" type of immunotherapy.These patients will be randomly assigned to receive anti-CD40 antibody, nivolumab or anti-CD40 antibody and nivolumab combination.In addition, during this process, all patients who have not previously received treatment for metastatic disease will also undergo standard chemotherapy.
In addition, clinical trials testing the combination of anti-CD40 antibodies with nivolumab for metastatic melanoma and lung cancer patients with ineffective checkpoint blockade are also in progress.Scientists hope that this approach will work even in the most difficult cancers.
Vonderheide, "We used these methods to try to break the" glass ceiling that can be achieved by immune checkpoint inhibitors."
5, Immune Checkpoint Inhibitors for Early Tumors
Researchers are also studying the effect of using immune checkpoint inhibitors in early cancers. Scientists believe that early tumors may not have developed a good defense against immune attacks, so immune checkpoint inhibitors may respond better to early tumors.
Dr. Suzanne Topalian of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, noted that last year nivolumab had received FDA approval for the adjuvant treatment of lymph node metastases after surgical resection in melanoma patients.
Topalian and some other scientists are also actively exploring the use of immune checkpoint inhibitors for the neoadjuvant treatment of various types of cancer.The immune checkpoint inhibitor moved from surgery to pre-surgery.Topalian's group recently published the results of a pilot study that reported for the first time data on the preoperative use of nivolumab in patients with untreated early stage NSCLC.
6, safety deserves attention
In addition, immune-related adverse events (irAEs) are also the focus of current research by scientists.Immune-related adverse events may occur in any organ, but most commonly in the skin, gastrointestinal tract, endocrine glands, and liver.
Most irAEs can be mitigated by dose modification, interruption of treatment, or use of steroids according to clinical practice guidelines.However, rare and irreversible conditions such as type 1 diabetes may still occur.Dr. Jeffrey Bluestone, professor at the University of California, San Francisco and CEO of the Parker Institute, said that the Parker Institute is developing a strategic plan to try to solve some of the problems surrounding irAE.
Bluestone also stated that the purpose of this strategic plan is to gain a deeper understanding of the biological, biochemical, and genetic basis behind these adverse events, thereby identifying which patients are at greatest risk of adverse events and trying to avoid them.In the process, a deeper understanding of the causes of type 1 diabetes in the absence of these therapies is also possible.
Although various barriers limit the efficacy and safety of checkpoint inhibitors, Bluestone highlights that these drugs have revolutionized cancer therapy.Above all, it's not over, it's just beginning.
Original: Immunotherapy 2.0: Improve the response to Checkpoint Inhibitors
Author: M.J. Friedrich