Immune Checkpoint Inhibition in Advanced Cancer
Michael Postow, MD, Memorial Sloan Kettering Cancer Center, New York, New York. USA
Fellow Summary
Authored by Adam DuVall
Dr. Postow’s talk was focused on critical areas of using immune checkpoint inhibition in advanced cancer that are most underdeveloped at this time and thus provide the greatest opportunities for fellows as they transition to junior faculty.
The first area is the use of immune checkpoint inhibitors in combination with other agents. Dr. Postow provided an example combining radiation to target lesions in combination with ipilumumab or radiation with ipilumumab and nivolumab. He showed how initial justification to combine RT+ipi came from an initial patient who had a good response; when it was used in a trial, it was not an effective combination, although it was also demonstrated that a decrease in TCR diversity was associated with response in the few individuals who did. However, he also described how the combination of RT+ipi/nivo was then investigated in preclinical models that seemed to show increased activity.
The second opportunity was to examine clinical or correlative study data more deeply than the initial clinical trial. An example of this looked back at the ipi/nivo versus ipi trial and attempted to examine the immune response further to determine why ipi/nivo had a superior response rate. Dr. Postow presented data indicating that combination therapy increased the Ki67 and TIM3 and CTLA4 expression in CD8+ T cells when compared to ipi monotherapy. The most remarkable part of this data was that it was seen after 1 dose of treatment. When this is combined with the clinical information that there is not a significant response rate in those who have to stop therapy early due to side effects, Dr. Postow described the protocol he wrote focused on de-escalation of therapy to investigate this effect further.
The third opportunity for fellow and junior faculty that Dr. Postow discussed was the goal of improving our understanding of the toxicities of immunotherapy. He presented work that examined the rates of grade 3-4 increases in lipase and amylase in comparison to rates of actual pancreatitis, overall treatment requirements, and studies that examined pneumonitis and skin related adverse events.
Overall, Dr. Postow’s presentation was excellent and gave practical advice to people early in their careers on how to get involved in research in immunotherapies. He also presented interesting preliminary data as personal examples which help emphasize his general themes.
Scholar Summary
Authored by Bridget Keenan
Dr. Postow laid out his talk from the lens of a fellow, highlighting general avenues for projects that can be undertaken during fellowship and have the potential to develop into career opportunities. Three examples he gave from his own career were: 1) provide data or a concept to justify a combination therapy, 2) study data (correlative or clinical) in greater depth than the initial clinical trial, and 3) improve understanding of toxicities. In the first example, he built off anecdotal evidence of a patient progressing on immunotherapy who had an abscopal response to radiation after they received an additional dose of ipilimumab (Postow and Callahan et al, NEJM, 2012). Radiation has several hypothetical possible mechanisms to augment immune responses to cancer, including creating an anti-oncogenic cytokine milieu, enhancing cross-presentation, activating endothelium, and promoting anti-tumor CD8+ T cell responses. His group was able to study this phenomenon in depth by analyzing tumor antigen-specific responses and immune cell subsets in this patient. The rationale for this combination led to a phase I clinical trial of radiation and ipilimumab in melanoma patients, which unfortunately showed that the majority of patients did not respond to this combination, but the preclinical work by the same group showed that PD-1/PD-L1 pathway may represent a resistance mechanism in mice treated with radiation and anti-CTLA4 (Twyman-Saint Victor et al., Nature, 2015). Additionally, they found that radiation can increase the diversity of the T cell receptor repertoire. There are additional ongoing trials by Dr. Postow and others to assess the combination of checkpoint inhibition and radiation.
In the second example, Dr. Postow has investigated the mechanisms of anti-CTLA4 and anti-PD-1 beyond that which was studied in clinical trials, including comparisons of combination therapy. Studying the blood of patients treated with ipilimumab, Dr. Postow and colleagues found that proliferating T cells were increased from baseline as early as one week into treatment (Postow et al, ASCO 2012). They similarly found that pembrolizumab could also increase CD8+ T cell proliferation, but that combination ipilimumab and nivolumab further increased proliferating T cells over ipilimumab monotherapy but can also upregulate immune checkpoints including CTLA-4 and Tim-3 (Postow et al, ASCO 2016).
In his final example, Dr. Postow noted that cohorts of patients treated with checkpoint inhibitors who had to discontinue therapy due to toxicity have similar overall and progression-free survival to patients who continued on immunotherapy (Schadendorf, JCO 2017). Based on this result, Dr. Postow and colleagues designed a trial that will prospectively test the hypothesis that patients with an initial response to therapy may not need continued treatment, potentially sparing them the increased toxicity risk that is associated with combined ipilimumab and nivolumab. Patients on this Phase 2 trial will receive two doses of combined ipilimumab and nivolumab and, based on the results of their 6 week scans, will enter either an arm with maintenance nivolumab or an arm with additional doses of the combination.
Fellow Summary
Authored by Galina Lagos
Dr. Michael Postow presented on immune checkpoint inhibition in advanced cancer with a focus on opportunities that may be available to fellows to contribute to and advance a developing field.
Immunotherapies depend on the ability of the immune system to recognize a tumor as foreign. However, tumors develop adaptive mechanisms through changes in the tumor cells themselves and their microenvironment to evade recognition by T cells. This resistant tumor microenvironment (TME) is described as being “cold”, and several strategies are being investigated to transition to a “hot” or inflamed TME to overcome immunotherapy resistance. One strategy that has emerged is the use of radiation, which can enhance inflammation by promoting cytokine release and activation of antigen presenting cells and enhance T cell production and infiltration of the tumor. As a fellow, Dr. Postow reported on a case of the abscopal effect, where cancer regresses at a location distant from the irradiated site, in a patient with melanoma who was treated with ipilimumab and radiation. Although the use of combination ipilimumab and RT did not demonstrate the same efficacy in a clinic trial, correlative studies from the case report and preclinical models suggested approaches to enhance efficacy, including through the addition of PD-L1 blockade. This is still an area of ongoing investigation.
The second portion of his talk focused on how fellows can use correlative and clinical data to contribute to a better understanding of the mechanisms of treatment response. Looking retrospectively at melanoma patients treated with ipilimumab, Dr. Postow and his colleagues identified T cell receptor diversity as a potential predictor of immunotherapy response. He also made observations regarding immunologic changes in T cell populations comparing CTLA-4 blockade alone versus combination with PD-L1 blockade, which may in part explain improved response to combination therapy. Finally, he discussed how observations from the clinic can be used to inspire trial design using the example of ongoing response to immunotherapy in patients who have to stop treatment early due to toxicity. He described how these observations inspired an ongoing trial he is now leading of de-escalating treatment, combination treatment with nivolumab+ipilimumab with fewer ipilimumab doses depending on treatment response.
In the final part of his presentation, Dr. Postow described how fellows can contribute to their field by enhancing our understanding of treatment toxicities. He used the example of describing toxicities related to immunotherapy treatment in melanoma as a valuable contribution that affects patient care. In summary, Dr. Postow provided very practical and inspirational advice on how we can get involved in various avenues of research while we are in our training that can have a significant impact on treatment approaches, trial design, and deepening our understanding on the mechanisms of drug response and resistance.
Fellow Summary
Authored by Everett Moding
Immune checkpoint inhibition has dramatically shifted the landscape of cancer treatment, and the clinical applications of immunotherapy continue to grow. Dr. Postow shared opportunities to perform translational research in an expanding field by describing his contributions to the field of immunotherapy.
As cancers develop within the tumor microenvironment, they evolve to avoid recognition by the immune system. One potential opportunity to improve the efficacy of immune checkpoint inhibition is to increase the visibility of tumors by the immune system. Radiation therapy may be particularly well-suited to increase the efficacy of immunotherapy by increasing cytokine secretion, antigen cross presentation, T cell production, and immune infiltration into tumors. By showing an early example of the abscopal effect in a patient treated with palliative radiation therapy while receiving ipilimumab for metastatic cancer, Dr. Postow sparked several clinical trials attempting to increase the efficacy of immunotherapy with radiation therapy. Though initial clinical efforts have failed to show a large effect, preclinical data continues to accumulate that radiation therapy and immunotherapy could be an advantageous combination.
Several studies have demonstrated that the combination of anti-CTLA-4 and anti-PD-L1 therapy improves outcomes over anti-CTLA-4 therapy alone, with the cost of more toxicities. However, stopping immune checkpoint inhibition due to autoimmune adverse events does not appear to adversely affect clinical outcomes in patients responding to treatment. A key effect of immune checkpoint inhibition appears to be increasing proliferation of T cells. T cell proliferation increases after the first dose of combined CTLA-4/PD-L1 blockade, but there does not appear to be a continued increased in T cell activation after subsequent doses. As a result, combined CTLA-4/PD-L1 blockade could be used to trigger initial immune responses prior to maintenance monotherapy to minimize toxicities. Dr. Postow is testing this possibility in a Phase II trial de-escalating combined CTLA-4/PD-L1 blockade by switching to maintenance anti-PD-L1 therapy in patients with a favorable response to combined therapy.
A final important opportunity for translational research is characterizing the toxicity of new therapies. The widespread use of immune checkpoint inhibitors has led to multiple autoimmune side effects that are very different from the toxicities associated with conventional cytotoxic therapies. As a result, there is an opportunity to describe these new toxicities such as pneumonitis and skin toxicity. When describing toxicities, it is important to separate lab abnormalities from clinically important side effects. For example, 20% of patients experience elevated lipase or amylase during immune checkpoint inhibition, but only 1% of patients have clinical pancreatitis. A better understanding of toxicities associated with immune checkpoint inhibition and approaches to limit or reverse adverse events could improve outcomes in patients treated with immunotherapy.
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