Combination Strategies for Jump-Starting the Immune Response


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CHECKPOINT INHIBITORS have dramatically changed the landscape of the treatment of melanoma, lung, bladder, and other cancers. Researchers are focusing on exploring ways to extend the use of checkpoint inhibitors to other disease states and to combine them with novel agents and improve outcomes. 

At the 2017 ASCO Annual Meeting, separate presentations explored novel combinations: pembrolizumab (Keytruda) combined with chimeric antigen receptor (CAR) T cells in relapsed pediatric acute lymphoblastic leukemia (ALL)1; navoximod (an indoleamine-pyrrole 2,3-dioxygenase [IDO1] inhibitor) in combination with atezolizumab (Tecentriq) in advanced solid tumors2; and a glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist alone or in combination with nivolumab (Opdivo) in patients with advanced solid tumors.3 

It is still early days, but all three approaches are yielding positive data in preliminary clinical studies. The search continues for reliable biomarkers to identify patients who are likely to respond to single-agent immunotherapy and combination therapy. 

Pembrolizumab and CAR T-Cell Therapy 

SIX PEDIATRIC PATIENTS with relapsed pediatric ALL were treated with pembrolizumab to augment response to CD19-specific CAR T cells. The scenario for each patient was slightly different. Some received murine CD19 CAR T cells initially, followed by humanized CD19 CAR T cells at relapse. Patients were reinfused with CAR T cells at relapse several times, with variable outcomes. Some patients were given one dose of pembrolizumab, and others were given pembrolizumab continuously every 3 weeks. In this early series, pembrolizumab every 3 weeks led to objective clinical responses and prolonged persistence of CAR T cells in three of six patients.


“The addition of PD-1 blockade has the potential to prolong CAR T-cell persistence and shows promising clinical activity.”
— Shannon Maude, MD

“We and others have shown complete response rates of 70% to 90% with CD19-specific CAR T cells that can persist for months or years and have the potential to mediate long-term disease control. But early recovery of normal B cells, indicating loss of CD19-directed CAR T cells, occurs in approximately 20% of patients and signals an increased risk of relapse. While the majority of patients receiving CTL019 (a murine CD19-directed CAR T-cell product) have prolonged persistence, early B cell recovery continues to be a problem for about 15% of patients who have a CD19-positive relapse after CAR T-cell infusion,” explained Shannon Maude, MD, of the Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine. 

“We are piloting ways to overcome that immune-mediated rejection of CAR T cells by using humanized CAR T cells [ie, CTL119], but we still see poor persistence of CAR T cells in some patients. Many patients can respond multiple times [to reinfusion of CAR T cells] but continue to have short persistence of CAR T cells,” Dr. Maude explained. 

NOVEL STRATEGIES FOR AUGMENTING IMMUNE RESPONSE

  • Three novel strategies hold promise for augmenting the immune response in patients with cancer: pembrolizumab added to CAR T cells in relapsed/refractory acute lymphoblastic leukemia; a glucocorticoid-induced tumor necrosis factor receptor agonist plus nivolumab in advanced cancers; and an IDO1 inhibitor plus atezolizumab in advanced cancers.
  • These are preliminary studies, and further study is ongoing for each of these strategies.
  • Biomarkers to determine response and select appropriate patients for therapy represent an unmet need.

For patients who continued to demonstrate short persistence after CAR T-cell reinfusion, checkpoint blockade with pembrolizumab was initiated, no earlier than day 14 after reinfusion. Some children received one dose of pembrolizumab following reinfusions, and three children were given continuous pembrolizumab every 3 weeks (two of them after first receiving murine CD19 CAR T cells followed by humanized CD19 CAR T cells, and a third patient was treated with pembrolizumab for partial response following initial murine CAR T-cell infusion). 

“In two patients who received pembrolizumab every 3 weeks, we see prolonged persistence of CAR T cells. In a separate patient treated with CAR T cells for the first time after relapse, when that patient progressed, pembrolizumab was given every 3 weeks, and we saw increased detection of CAR T cells in the blood and a decrease in positron-emission tomography (PET)-avid disease, which continued to decrease over time,” she told the audience. 

“The addition of programmed cell death protein 1 (PD-1) blockade has the potential to prolong CAR T-cell persistence and shows some promise, with objective clinical responses in three of six patients, and it can be added safely,” she stated. There were two cases of fever, two cases of cytopenias, and no case of severe cytokine-release syndrome. 

GITR Agonist and Nivolumab 

ANOTHER NOVEL COMBINATION therapy is the use of a glucocorticoid-induced tumor necrosis factor receptor agonist (BMS-986156) in combination with nivolumab for the treatment of advanced solid tumors. “This fully humanized agonist binds with high affinity to GITR, promotes T-regulatory cell depletion, leading to increased T-effector cell activity,” explained lead author Lillian L. Siu, MD, FASCO, of the Princess Margaret Cancer Centre in Toronto. 

Promising preclinical data showed synergistic antitumor activity in a murine tumor model with an anti–glucocorticoid-induced tumor necrosis factor receptor agonist plus an anti–PD-1 inhibitor. This led to a phase I and II study of BMS-986156 monotherapy in escalating doses and a parallel combination study with the combination of BMS- 986156 plus nivolumab every 2 weeks in escalating doses.2 


“These data support the evaluation of this combination [the GITR agonist BMS-986156 plus nivolumab] in future studies.”
— Lillian L. Siu, MD, FASCO

At the 2017 ASCO Meeting, Dr. Siu reported the results of the dose-escalation arms for 29 patients treated with monotherapy and 37 patients treated with combination therapy with a variety of solid tumor types. One-third of the monotherapy arm and one-half of the combination therapy arm had at least three or more prior lines of therapy (seven patients and five patients, respectively, had previous anti–PD-1 or PD-L1 therapy). 

Of 37 patients, 5 (14%) in the combination arm responded in this first study of an anti-glucocorticoid-induced tumor necrosis factor receptor antibody and a PD-1 inhibitor (nivolumab), including 2 patients whose disease progressed on or after prior anti–PD-1 therapy. Toxicity was manageable at a dose of 240 mg of BMS-986156 with 240 mg of nivolumab, with no dose-limiting toxicity. 

“These data support the evaluation of this combination in future studies,” Dr. Siu said. 

Navoximod Plus Atezolizumab 

A PRELIMINARY PHASE Ib study evaluated the use of the combination of the IDO1 inhibitor navoximod and atezolizumab in 61 patients with 15 different types of advanced solid tumors. Breast, ovarian, colorectal cancer, and endometrial cancers were the most common tumor types. The median number of prior therapies was three, and the median duration of treatment was 51 days. A total of 47 patients discontinued treatment due to disease progression, and 1 patient stopped treatment due to an adverse event. The maximum tolerated dose of navoximod was not reached in this trial, and the treatment was generally well tolerated. 


“The combination of navoximod and atezolizumab was well tolerated, with no maximum tolerated dose reached.”
— Howard A. Burris III, MD

There were six partial responses in various tumor types. Dr. Burris described two representative cases. One patient, who had pancreatic cancer and concurrent Lynch syndrome and was previously treated with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) and FOLFOX (leucovorin, fluorouracil, oxaliplatin), achieved tumor reduction of 30% by day 37 of treatment with the combination therapy. This patient has been on treatment for more than 1 year, and response is ongoing at the time of data cutoff. The second patient, who had platinum-resistant ovarian cancer, had a 41% reduction in target lesion by day 184, with significant decline in CA-125 antigen. 

No clear association was observed between response and programmed cell death ligand 1 (PD-L1) expression or IDO1 expression. 

“The combination of navoximod and atezolizumab was well tolerated, with no maximum tolerated dose reached. Treatment-related grade 3 and higher adverse events and treatment discontinuations were within the range of what we see with single-agent atezolizumab. We are now enrolling patients in an expansion phase with navoximod at 600 mg and 1,000 mg twice daily in combination with atezolizumab,” said lead author Howard A. Burris III, MD, President and Chief Medical Officer of the Sarah Cannon Research Institute in Nashville. ■

DISCLOSURE: Dr. Maude has served as a consultant or advisor to Novartis and received research funding from Novartis. Dr. Siu has served as a consultant or advisor to AstraZeneca/MedImmune, Boehringer Ingelheim, Celgene, Merck, and Pfizer and has received research funding from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, MedImmune, Merck, Novartis, and Pfizer. Dr. Burris reported no conflicts of interest. 

REFERENCES 

1. Maude SL, Hucks GE, Seif AE, et al: The effect of pembrolizumab in combination with CD19-targeted chimeric antigen receptor (CAR) T cells in relapsed acute lymphoblastic leukemia. 2017 ASCO Annual Meeting. Abstract 103. Presented June 4, 2017. 

2. Siu LL, Steeghs N, Meniawy T, et al: Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in patients with advanced solid tumors. 2017 ASCO Annual Meeting. Abstract 104. Presented June 4, 2017. 

3. Burris HA, Gordon MS, Hellmann MD, et al: A phase Ib dose escalation study of combined inhibition of IDO1 (GDC-0919) and PD-L1 (atezolizumab) in patients with locally advanced or metastatic solid tumors. 2017 ASCO Annual Meeting. Abstract 105. Presented June 4, 2017.


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