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CAR T-cell therapy shows promise for mesothelin-expressing solid tumors
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ATLANTA — Intrapleurally administered, mesothelin-targeted chimeric antigen receptor T cells demonstrated antitumor activity without major toxicity among patients with malignant pleural disease from mesothelioma, according to results of a phase 1 trial presented at American Association for Cancer Research Annual Meeting.
Further, combining these mesothelin-targeted CAR T cells with anti-PD-1 therapy induced encouraging clinical outcomes, results showed.
“Our goal is to design a CAR to be effective against cancer cells, but spare normal cells,” Prasad S. Adusumilli, MD, deputy chief of thoracic surgery at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “While exploring several antigens, we observed that, a) mesothelin is expressed in majority of solid tumors, with very low levels in normal tissue; b) mesothelin expression imparted aggressiveness to cancer cells; c) mesothelin expression is associated with increased metastases and decreased survival; and d) there are isolated reports that generating immunity against mesothelin can be beneficial. Based on these characteristics, we chose mesothelin.”
Adusumilli and colleagues engineered mesothelin-targeted CAR T cells — IcasM28z — with the Icaspase-9 safety “suicide” switch, which, in the event of an unexpected toxicity, can be activated to kill all the CAR T cells in the patient’s body. The CARs target mesothelin, a cell-surface antigen that is highly expressed in malignant pleural disease — with low expression in normal tissues — and is associated with tumor aggressiveness and poor survival.
Malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease from lung and breast cancers occurs among more than 150,000 patients a year in the U.S. However, Adusumilli and colleagues estimated that at least 2 million patients with solid tumors in the U.S. would be eligible for this therapy. The mesothelin antigen is expressed in 90% of mesotheliomas, 60% of lung cancers, 35% of triple-negative breast cancers, 70% of pancreatic cancers, and 60% of ovarian cancers, as well as in patients with stomach, colon, and other solid tumors.
Researchers evaluated the safety and maximum tolerated dose of these CAR T cells in 21 patients with biopsy-proven malignant pleural disease expressing mesothelin, including 19 patients with malignant pleural mesothelioma and one each with lung and breast cancer. Forty percent of patients had received three or more lines of prior therapy.
Eighteen patients received cyclophosphamide preconditioning. Afterward, researchers used an interventional radiology procedure to inject the IcasM28z CAR T cells directly into the pleural cavity.
No CAR T-cell therapy-related toxicities occurred higher than grade 2, and there was no case of neurotoxicity or cytokine release syndrome. One patient experienced grade 3 febrile neutropenia related to cyclophosphamide.
Researchers also monitored patients for on-targeted, off-tumor toxicity by assessing chest or abdominal pain, pericardial effusion and ascites with CT/PET or echocardiogram, troponin elevation, and electrocardiogram evaluations, but found no evidence of toxicity.
This favorable toxicity profile is built on preclinical studies and researchers’ prior analyses of 2,000 patients with solid tumors, Adusumilli said.
Based on that research, Adusumilli and colleagues genetically engineered the CAR to be effective against cancer cells while sparing normal cells, to be armored with a potent co-stimulation without the need for help from other immune cells, and to be the first CAR to be developed from all human genetic components so the immune system won’t reject it in the long term.
“More importantly, as our clinically relevant mouse models showed that CAR T cells infused through blood are getting sequestered in the lungs for few days — which may lead to toxicity — and not able to enter the tumor mass efficiently, we investigated and translated a strategy of directly injecting CAR T cells into the chest cavity where the tumor masses are (using CT scans and ultrasound), thereby avoiding toxicity and increasing efficacy several folds,” Adusumilli told HemOnc Today. “This approach is first in the world.
“In brief, by understanding the ‘battlefield’ (tumor environment), by making better CAR with genetic engineering (‘precision tool/weapon with no collateral damage’), by strategizing the ‘landing’ (delivery approach), and by providing ‘allies’ (appropriate timely support), we were able to move forward in the fight against the cancer,” he added.
Thirteen patients had detectable CAR T cells in their peripheral blood — measured by vector copy number — from day 1 to 38 weeks after infusion. T-cell persistence appeared associated with a 50% or greater serial serum soluble mesothelin-related peptide levels and evidence of tumor regression.
One patient with mesothelioma underwent successful curative-intent surgical resection 6 weeks after CAR T-cell infusion.
Preclinical studies showed that CAR T cells became functionally exhausted while residing in large tumors, and that treatment with anti-PD-1 agents could reactive these T cells. Thus, after researchers had observed no toxicity 6 to 17 weeks after CAR T-cell infusion, 14 patients received one to 21 cycles of anti-PD-1 checkpoint blockade agents off protocol as next line of therapy.
“These CAR T cells upregulate PD-1 and tumor cells start expressing PD-L1 for immune escape,” Adusumilli told HemOnc Today. “We were able to rescue exhausted CAR T cells by administration of anti-PD-1 agent and prolong the functional persistence and survival of the mice [in the preclinical studies]. This led to our clinical translation.”
Two patients achieved complete metabolic response — ongoing at 60 and 32 weeks — on PET scan, five patients achieved partial response and four patients achieved stable disease.
“It is surprising to many clinicians and scientists is to be able to see such responses in therapy-resistant solid tumors with one dose of CAR T cells,” Adusumilli said.
Based on emerging data from the clinical trial demonstrating the benefit of anti-PD1 strategy, Adusumilli and colleagues are moving this research a step forward, he said.
“As anti-PD-1 agents are not targeted to tumors and can cause toxicity, we generated a ‘decoy’ receptor — PD-1-dominant negative receptor (DNR) that can be incorporated within the CAR. This new construct — mesothelin-targeted CAR with built-in PD-1 DNR — is now in investigational new drug studies with a plan to open the trial in early 2020,” he said.
Patients with therapy-resistant mesothelioma on the trial who are now receiving anti-PD-1 agents, as well as newly recruited patients, are asking whether they can receive the PD-1 DNR construct to avoid taking anti-PD-1 infusion every 3 weeks for the rest of their life, Adusumilli added.
“The research question is which strategy is better in enhancing potency without toxicity,” he said. “What will be the ‘next move’ of the tumor to suppress CAR T-cell efficacy and how can we overcome it?”
Because this is an early, phase 1 trial, long-term efficacy of this therapy has not been established, Adusumilli said. – by Alexandra Todak
Reference:
Adusumilli PS, et al. CT036. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: Adusumilli reports research funding from Atara Biotherapeutics, which received the license of mesothelin CARs from Memorial Sloan Kettering Cancer Center. Adusumilli and another researcher are the inventors of this therapy and will receive a share of the license income. Memorial Sloan Kettering received license fees and has the potential to receive royalties under the license. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to TopJorge Nieva, MD
I would agree these are the best data we have so far for CAR T-cell therapy in solid tumors.
Most CAR T cells go after targets of cancer cells that can’t be attacked without risk for toxicity. What is most exciting about this particular treatment is that it did not cause undue pleural or other organ toxicity against a target that is fairly widely distributed in the body. The finding of many patients achieving long-term, stable disease is wonderful. And this treatment is likely to lead to benefit for patients beyond those with mesothelioma, because we know many other solid tumors also express mesothelin.
Some of the limitations of the study include that many of the patients who achieved durable benefit received the CAR T-cell therapy in combination with checkpoint inhibition therapy. We know that checkpoint inhibition therapy has measurable response rate in mesothelioma, so it’s very difficult from this study to deconvolute the effects of the CAR T-cell therapy from the effects of the checkpoint inhibitor. Nonetheless, the combination may be viable moving forward.
The other thing to keep in mind is that it’s very difficult to measure radiographic response in mesothelioma. So, it will be important to understand what happens with further long-term follow-up with those patients who have had stable disease to really understand the durability of disease control with this strategy.
Moving forward, I would like to see CAR T-cell therapy expanded into other mesothelin-positive tumors. I would also like to have a better understanding of the pleural delivery mechanism as opposed to IV delivery for the therapeutic.
Perspective
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Saul Priceman, PhD
This exciting CAR T-cell study by Adusumilli and colleagues evaluated mesothelin-directed CAR T cells for the treatment of patients with mesothelioma.
In this trial, CAR T cells were engineered with a safety “suicide” switch that could induce rapid CAR T-cell killing if unexpected toxicity was observed. Additionally, CAR T cells were infused regionally into the pleural cavity as opposed to systemically. This route of administration was demonstrated in preclinical studies to reach sites of disease more rapidly and showed improved antitumor activity compared with systemic IV delivery of CAR T cells.
In general, a more locoregional approach is an exciting move for amenable diseases like brain tumors, mesotheliomas and peritoneal disease. We are using this approach in a phase 1 CAR T-cell clinical trial at City of Hope for patients with HER2-postive breast cancer that has spread to the brain.
The Memorial Sloan Kettering Cancer Center trial treated 21 patients, and one patient experienced a durable antitumor response and went on to curative surgery. Fourteen patients went on to receive anti-PD-1 checkpoint blockade therapy, which improved overall responses in a subset of patients.
Although the results of these two trials are preliminary, it is exciting to see early safety and promising efficacy data being presented in solid tumors with CAR T cells, optimizing the therapy with locoregional delivery, lymphodepleting preconditioning regimens and incorporation of suicide switches for safety. This study will likely be joined by many others over the next few years and will undoubtedly advance our understanding of the potential for CAR T-cell therapy in the treatment of solid tumors.
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