Kevin Mayer Senor Editor Genetic Engineering & Biotechnology News

While Successes Have Been Reported, Not all Patients Respond to Immuno-oncology Drugs and That Needs to Be Studied Further

At a recent cancer immunotherapy conference—Translating Science into Survival—several presenters started their sessions by announcing, not at all sheepishly, that they planned to say little or nothing about cancer. These presenters were the exception, but still, their shamelessness might have surprised anyone who was expecting to hear about cancer immunotherapy’s clinical triumphs.

To be fair, most of the conference’s sessions aligned with the reasonable expectation that cancer immunotherapy is still full of promise, even if it is occasionally overhyped. If cancer immunotherapy seems to be advancing more slowly than we would like, it should be remembered that it is also advancing along a broad front, one that stretches over varied terrain, from the tumor microenvironment to the microbiome, with long marches along metabolic pathways and extended patrols for neoantigens.

The state of cancer immunotherapy was discussed by a panel of speakers who were assembled to summarize the insights that were provided by the Translating Science into Survival conference. While the speakers did mention specific insights, they were at pains to emphasize a broader point: Now that cancer immunotherapy has emerged as the fourth pillar of cancer treatment—standing alongside chemotherapy, radiotherapy, and surgery—it is time for the field to address a new set of questions. These questions are, by necessity, so detailed and so numerous that they may not seem parts of a coherent line of inquiry, at least, not to casual observers or the parties responsible for the government’s research funding.

Given the conference’s venue—midtown Manhattan—an analogy involving real-estate development comes to mind. When a construction of a new skyscraper begins, the building site is cordoned off, and posters appear that depict the finished tower in all its gleaming glory, which contrasts almost ignominiously with the current reality: a giant hole in the ground. Yet most passersby come to realize that the higher a building is to rise, the deeper its foundations must reach. Also, once progress on such a building becomes obvious, time to completion seems to pass surprisingly quickly. Finally, after the building is complete and the scaffolding is removed, it can seem as though the building had always been there.

Although they expressed their thoughts less metaphorically, the panel’s participants did dwell on the importance of foundational work, as well as its ultimate rewards. For example, Jill O’Donnell-Tormey, Ph.D., CEO and director of scientific affairs, Cancer Research Institute (CRI), noted that basic bioscience is driving cancer immunotherapy by improving the mechanistic understanding of therapeutic targets. (She also noted that it was fitting that a discussion of the tumor microenvironment at the conference should emphasize the stroma, not cancer, since the tumor microenvironment is not just about the interplay of cells, but also the creation of a physical barrier.)

Another panel participant, Elizabeth Jaffee, M.D., deputy director, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, emphasized the dynamic nature of cancer immunotherapy and how effective treatments may need to orchestrate multiple modalities, in sequence or all at once. For example, a sequential approach may be needed to cope with the rise of new mutations as a cancer evolves, or multiple inhibitors may have to be deployed simultaneously to make a success of checkpoint inhibition.

With either scenario, noted panel moderator Philip Greenberg, M.D., head of the program in immunology, Fred Hutchinson Cancer Research Center, it would be necessary to consider how many targets could be attacked without exceeding a patient’s tolerance for adverse side effects. Ultimately, Dr. Greenberg summarized the questions that the cancer immunotherapy field needs to address going forward:

  • Which approaches work best for certain patients?
  • Which treatment combinations might work?
  • How, for a given patient, might treatment evolve as it begins to work, or not?
  • How might treatments be personalized?

All of the panelists were sensitive to the issue of funding. For example, Dr. Greenberg observed that in general funding has been flat. Moreover, funding priorities have not kept pace with the growing awareness of cancer immunotherapy’s potential. Dr. O’Donnell-Tormey added that while organizations such as CRI can provide catalytic funding, they cannot substitute for systematic, programmatic support of the kind that only government funding can provide.

In contrast with the panel’s uncertainty over funding was its confidence that cancer immunotherapy is already demonstrating clinical relevance. For example, the panel highlighted two presentations, each of which suggested ways in which cancer immunotherapy is becoming more refined and, not incidentally, more effective. One presentation summarized a recent study about the monitoring of a cancer immunotherapy’s effectiveness. Another presentation described recent success with a combination immunotherapy.

Monitoring Patient Response to a Checkpoint Immunotherapeutic

The monitoring study indicated how clinicians might detect, in a convenient and timely way, whether a cancer immunotherapy is working. Doing so would be important, given that a particular treatment may not work well with all patients. Unresponsive patients should be quickly switched to other treatments without delay.

According to Alexander Huang, M.D., a clinical fellow at the Perelman School of Medicine at the University of Pennsylvania, it is possible to monitor a patient’s response to pembrolizumab, a checkpoint inhibitor drug, by assessing the effect of the drug on immune cells in blood samples. Among patients with stage IV melanoma who were being treated with pembrolizumab, the ratio of a particular subset of immune cells in the blood to tumor burden correlated with clinical response.

Dr. Huang and colleagues analyzed blood samples from 29 patients with stage IV melanoma taken before and at 3, 6, 9, and 12 weeks after starting treatment with pembrolizumab. They measured levels of the proliferation marker Ki67 in immune cells called exhausted-phenotype CD8-positive (CD8+) T cells.

“After a prolonged battle with tumor cells, CD8+ T cells become progressively more dysfunctional, or exhausted,” explained Dr. Huang. “Exhausted-phenotype CD8+ T cells have high levels of the protein PD-1 on their surface. Pembrolizumab targets PD-1. In preclinical models, pembrolizumab targeting of PD-1 can reinvigorate exhausted-phenotype CD8+ T cells, something that we can measure by increased levels of proliferation markers like Ki67.”

The researchers found that levels of Ki67 were significantly greater in CD8+PD-1+ T cells (exhausted-phenotype CD8+ T cells) in posttreatment blood samples compared with pretreatment blood samples for 78 percent of patients. A clinical response, as measured by immune-related RECIST criteria, occurred in 38 percent of patients.

Dr. Huang and colleagues measured the level of Ki67 in CD8+PD-1+ T cells before and after treatment, with the peak Ki67 after treatment considered the measure of the extent of reinvigoration of exhausted-phenotype CD8+ T cells. They then found that the ratio of CD8+PD-1+ T cell reinvigoration to pretreatment tumor burden correlated with clinical response. In one cohort of patients, all those who had a ratio greater than 1.94 were alive after 11 months of follow-up compared with 50% of patients with a ratio of less than 1.94. In a second cohort, 75% of patients with a ratio greater than 1.94 were alive at two years, compared with 29 percent with a ratio less than 1.94.

“We were excited to find that patients with a balance in favor of the immune response compared to tumor burden were more likely to have clinical benefit,” said Dr. Huang. “If validated in larger studies, this could provide a way to predict early on after starting pembrolizumab treatment whether a patient should continue this treatment or either change to a different treatment or add an additional treatment.”

Combining Immunotherapies to Achieve Durable Tumor Responses

A combination of the immunotherapies AM0010 and the immune checkpoint inhibitor pembrolizumab was not only well tolerated, it also resulted in durable objective tumor responses in advanced solid tumors. These results, which pertained to patients with renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), were presented by Aung Naing, M.D., an associate professor at The University of Texas MD Anderson Cancer Center in Houston.

“Immunotherapy has improved the prospects for many cancer patients by providing long-term benefit, but not all patients respond to the currently available immuno-oncology drugs,” said Dr. Naing. “Rational combinations of immune therapies are likely to expand the tumor-specific immune activation and lead to more durable tumor responses.”

Dr. Naing described a multi-cohort Phase I clinical trial in which 19 patients with advanced melanoma, RCC, or NSCLC were enrolled a cohort in which patients received one of the two doses of AM0010 daily and 2 mg/kg body weight pembrolizumab every three weeks. After 10 to 15 months of observation, two of the eight patients with RCC had a complete reduction of their tumor burden (complete responses) and two had a 77% and a 92% reduction (partial responses (PR)), respectively. Of the six melanoma patients, two had PR, and two others had an initial increase in tumor volume followed by a decrease (known as pseudoprogression).

The targets of AM0010 and pembrolizumab, IL-10 receptor and PD-1, respectively, are both present on CD8+ T cells. AM0010 enhances the survival and tumor cell-killing activity of CD8+ T cells and complements the activity of pembrolizumab that blocks the immune-suppressive PD-1/PD-L1 pathway, thus providing a rationale for this combination, Dr. Naing explained.

“In this clinical trial, we found that the two immunotherapies were well tolerated, without overlapping toxicity or severe autoimmunity, while providing strong antitumor responses,” noted Dr. Naing. “In addition, we detected new, expanding T-cell clones in the blood of all patients who received AM0010. Many of those T-cell clones were not detectable before treatment. This is reminiscent of tumor-specific vaccination.”

AM0010 is a PEGylated form of the recombinant human cytokine IL-10. This therapy has specific immune-stimulating effects that induce the activation, proliferation, and survival of cytotoxic CD8-positive (CD8+) T cells present within tumors. The weapons used by CD8+ T cells in killing cancer cells are the cytotoxic molecules—granzymes, FasL, and lymphotoxin beta. With AM0010 treatment, the levels of these cytotoxic molecules were elevated in the serum of the patients. This effect, Dr. Naing asserted, provides further evidence of the systemic activation of the cytotoxic arm of the immune system.


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