Predicting If an Immune Checkpoint Drug Will Work


Drugs that activate the immune system to attack cancer in a process known as immune checkpoint blockade (ICB) are a focus of intense investigation. A number of them are already approved by the U.S. Food and Drug Administration (FDA) for various cancers; namely, the anti-CTLA4 antibody ipilimumab (Yervoy), two anti-PD-1 antibodies: pembrolizumab (Keytruda) and nivolumab (Opdivo), and three anti-PD-L1 drugs: atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These ICB drugs have the potential to induce durable cancer regressions, but the majority of cancer patients just do not respond to them at all.

Biomarkers, signature molecules in the blood or other tissue, can sometimes be used to predict a patient’s response to a given treatment. But no reliable biomarkers exist for ICB, and this is a serious concern. Patients who may really benefit from ICB could be overlooked, and patients who are not likely to respond may receive useless (and very expensive) ICB treatment.

Most potential response predictors that have already been identified are not yet useful for one or all of the following reasons: they are not extensively validated, their significance is still uncertain and may differ from one cancer (or even one patient) to another, or they are technically challenging for routine use. These markers are addressed below. Continue reading…


Expert Discusses Promise of Immunotherapy in TNBC

Excerpt:

“The combination of immunotherapy and chemotherapy is showing promising response rates in certain patients with triple-negative breast cancer (TNBC), said ESO Umberto Veronesi Memorial Award Winner Giuseppe Curigliano, MD, PhD, who addressed genetic determinants of breast cancer immunogenicity in his award lecture at the 15th St. Gallen International Breast Cancer Conference.

“Curigliano emphasized the importance of patient selection in optimizing immunotherapy in breast cancer. In a study done by Curigliano, in collaboration with the Sidra Medical Center in Qatar, a subgroup of patients with TNBC who would derive benefit from checkpoint inhibitors were identified. This group, he stated, should be selected based on individual assessment of tumor-infiltrating lymphocytes.”

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Total Body Irradiation Did Not Improve Response of Adoptive Cell Transfer

Excerpt:

“Adding total body irradiation to preparative lymphodepletion chemotherapy prior to the adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) had no effect on tumor regression in patients with metastatic melanoma, according to the results of a study published in the Journal of Clinical Oncology.

“However, adoptive cell transfer of TILs did mediate the objective complete response of 24% of patients.

“ ‘The nonmyeloablative chemotherapy regimen thus seemed to provide sufficient lymphodepletion for successful adoptive transfer without the need to add total body irradiation,’ wrote researchers led by Stephanie L. Goff, MD, of the National Cancer Institute.”

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Expert Discusses Promise of CRS-207 Vaccine in Mesothelioma

Excerpt:

“The investigational cancer vaccine CRS-207 may improve response and survival when given with chemotherapy in patients with malignant pleural mesothelioma (MPM) according to results of a phase Ib trial.

“CRS-207, a live-attenuated, double-deleted Listeria monocytogene engineered to express the tumor-associated antigen mesothelin, was administered with chemotherapy to 38 patients with MPM. Of 34 evaluable patients, 59% (n = 20) had partial response posttreatment and 35% (n = 12) had stable disease, for an overall disease-control rate 94%. Median progression-free survival was 8.5 months and median overall survival had not been reached.

“Immunohistochemistry data from 3 patients revealed an increase in tumor-infiltrating lymphocytes (TILs) post–CRS-207. Treatment-associated changes in circulating immune cells and biomarkers were also observed.”

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TILs Advancing as Melanoma Immunotherapy Option

Excerpt:

“After nearly 30 years of research, tumor-infiltrating lymphocyte (TIL) technology is being investigated as a means of producing personalized immunotherapy for patients with metastatic melanoma in a small clinical trial that may help open the door for broader application in other solid tumor types.

“The form of adoptive cell therapy, which utilizes TILs from the patient’s tumor, represents an intriguing way of overcoming the immunosuppressive power of cancer, according to Jeffrey S. Weber, MD, PhD. The melanoma expert provided an overview of the technology and its potential benefit in a lecture for oncologists and oncology professionals presented by Targeted Oncology, a division of MJH Associates, the publisher of OncologyLive, on February 19 in Miami Beach, Florida. Weber is the deputy director of the Laura and Isaac Perlmutter Cancer Center, co-director of its melanoma program, and head of Experimental Therapeutics at NYU Langone Medical Center.”

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After Decades of Research, Potential for TILs in Melanoma Is Higher Than Ever

“Tumor infiltrating lymphocyte (TIL) technology represents an intriguing way of overcoming the immunosuppressive power of cancer, according to Jeffrey S. Weber, MD, PhD.

“Weber provided an overview of the technology and discussed its potential benefit to oncologists and oncology professionals in a lecture presented by Targeted Oncology on February 19, 2016.

“ ‘It’s yet another way of inducing remissions of long duration using an immunotherapeutic approach that’s different than ipilimumab and different than nivolumab or pembrolizumab,’ said Weber, the deputy director of the Laura and Isaac Perlmutter Cancer Center, co-director of the Melanoma Program, and head of Experimental Therapeutics at NYU Langone Medical Center. ‘It’s got its own toxicity, but you can fail this therapy and respond to ipilimumab or respond to nivolumab or pembrolizumab. You can fail nivolumab or pembrolizumab or ipilimumab and respond to this—they’re not cross-reactive.’ “


HER2-Positive Breast CA Patients Prosper on Solo Chemo

“Prognosis for human epidermal growth factor receptor 2 (HER2)-positive patients with lymphocyte-predominant breast cancer (LPBC) was significantly better following treatment with chemotherapy alone than it was for their counterparts receiving chemotherapy plus trastuzumab (Herceptin), an exploratory analysis of the North Central Cancer Treatment Group-N9831 trial has shown.

“Among 489 patients from the N9831 trial receiving chemotherapy alone, 10-year Kaplan-Meier estimates for recurrence-free survival (RFS) among participants with high-levels of stromal tumor-infiltrating lymphocytes (STILs) was 90.9% compared with 64.5% for patients with low-levels of STILs.

“In dramatic contrast, 10-year estimates for RFS among 456 patients who received the same chemotherapy regimen followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone were virtually identical in patients with high- and low-levels of STILs at 80% and 80.1%, respectively (HR 1.26; 95% CI 0.50-3.17; P=0.63).”


Higher Tumor-Infiltrating Lymphocyte Level Associated With Better Outcomes in HER2-Positive Early Breast Cancer Independent of Neoadjuvant Treatment

“In an analysis of the NeoALTTO trial reported in JAMA Oncology, Salgado et al found that a higher level of tumor-infiltrating lymphocytes was associated with improved pathologic compete response rate and event-free survival independent of neoadjuvant treatment received in patients with HER2-positive early breast cancer.

“In NeoALTTO, 455 patients were randomly assigned to receive neoadjuvant trastuzumab (Herceptin), lapatinib (Tykerb), or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks and three cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. Percentage of tumor-infiltrating lymphocytes were measured by hematoxylin-eosin stained core biopsy sections taken at diagnosis.”


High TIL Levels Predict Positive Outcomes in HER-2–Positive Breast Cancer

“High levels of tumor-infiltrating lymphocytes served as an independent positive predictive marker for EFS and pathological complete response in HER-2–positive early breast cancer treated with chemotherapy and anti-HER–2 agents, according a secondary analysis of the NeoALTTO trial.

“ ‘Increasingly, oncogenic addiction, in which tumors become dependent on a sole oncogenic pathway for growth, is thought to promote a tumor microenvironment conducive to immune escape,’ Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne, and colleagues wrote. ‘Although this had not been shown yet for HER-2 oncogenic signaling, one could speculate that anti-HER–2 therapy may not only work in a cell-intrinsic manner but may also reserve HER-2–induced immunosuppression as a mechanism for action.’

“The NeoALTTO trial included 455 women with HER-2–positive early-stage breast cancer between 2008 and 2010. The researchers randomly assigned patients to neoadjuvant treatment with trastuzumab (Herceptin, Genentech), lapatinib (Tykerb, GlaxoSmithKline) or both.

“Patients received the initial treatment for 6 weeks, followed by weekly paclitaxel for 12 weeks and three treatment cycles of fluorouracil, epirubicin and cyclophosphamide after surgery.”