Top stories from AACR 2019
By Rajaneesh K. Gopinath, Ph.D.
Precision medicine, emerging immunotherapies and data from key clinical trials were the talking points of the American Cancer Research Organization’s Annual meeting held at Atlanta from Mar 29 – Apr 3. Thousands of participants from various organizations converged to share the results of their continuous efforts to fight different cancers. Here’s a list of major highlights from the event.
Cancer is a major burden on public health and is one of the leading causes of mortality worldwide. Multiple approaches such as surgery, radiation, and chemotherapy have been employed over the years to combat the illness. However, those attempts have been met with mixed results. Today, immunotherapy which represents the engineering of one’s own immune cells to contain tumor metastasis is turning out to be an effective solution. The Chimeric Antigen Receptor (CAR) T cell therapy is one such, wherein T cells obtained from the patient are modified and infused back into the bloodstream to specifically bind to a cell surface antigen and destroy tumors. In the past few years, this approach enjoyed much progress in treating leukemia and lymphoma. Two well-known FDA approved CD19 directed CAR T cell therapies are Novartis’s Kymriah (Tisagenlecleucel) and Kite pharma’s Yescarta (Axicabtagene ciloleucel) which showed significant control of cancer progression.
CAR T Cell Trogocytosis Results in Fratricide and Enables Antigen Escape
Despite such advances, many patients still do not respond to these therapies due to mounting challenges like tumor resistance, heterogeneity and antigen escape. Patients who underwent CD19 directed CAR T cell therapies often relapsed with CD19-negative tumors. Similarly, tumors also exhibited an antigen-low condition, where CAR T cells when reintroduced became ineffective due to the low density of antigen present on the tumor cell surface. As a result, tumors escaped from the killing induced by CAR T cells. Unlike antigen loss, the underlying mechanism behind the antigen-low phenomena has eluded the scientific community for long.
Recently, a team from the Memorial Sloan-Kettering Cancer Center has found that after the initial CAR T treatment, cancer cells can transfer their antigens to CAR T cells and evade immunotherapy. Using leukemia mouse models, Dr. Mohamad Hamieh and team from Michel Sadelain’s lab demonstrated that through a process called trogocytosis, the target antigen of tumors is transferred to T cells, thereby reducing antigen density. This promotes fratricide where CAR T cells kill each other, leading to T cell exhaustion. The authors found that these mechanisms affected both CD28- and 4-1BB-based CARs. The results of this study were discussed in the session titled “Mechanisms of tumor escape from CAR therapy” and was published in Nature last March.
Overcoming Tumor Resistance
One of the talks in the opening plenary session was delivered by Crystal L. Mackall, MD, of Standford University on the topic “Next-generation CAR T cells designed to overcome tumor resistance”. Dr. Mackall detailed the clinical trials that are currently testing the bivalent CD19/CD22-targeted CAR T cells with the aim of surmounting the issue of antigen-negative tumors. She discussed her work on determining the factors that lead to T cell exhaustion, using in vitro models. She shared her lab’s discovery of overexpressed transcriptional factors in the exhausted T cells that inhibit their activation. Interestingly, they found that C-Jun overexpression reactivates those T cells and restores the balance. The overexpression also helps the T cells recognize antigen-low tumors.
Emerging CAR T- cell therapies for advanced solid tumors
The current focus of the medical community is to replicate the success of CAR T cell therapies in solid tumors. To that end, encouraging results of two preliminary trials were presented in the inaugural press conference.
1) Treatment of Malignant Pleural Disease Using Mesothelin Targeted CAR T Cells
Prasad S. Adusumilli, MD, thoracic surgeon at the Memorial Sloan Kettering Cancer Center presented data from a phase I study that tested the efficacy of mesothelin targeted CAR T cells in treating solid tumors. Over 150,000 patients in the US develop pleural cancers, ranging from mesothelioma to solid cancers of the lung and breast that metastasizes to the pleural cavity.
“Mesothelioma is an aggressive form of cancer for which existing therapies like surgery, chemotherapy or radiation only yield a median survival of 9-17 months”. The checkpoint blockade, anti-PD1/PD-L1 immunotherapies too showed mediocre endpoints. Hence, Adusumilli, senior author Michel Sadelain, MD, PhD, and team developed CAR T cells against the antigen, Mesothelin. Previous studies in mice demonstrated that their second-generation CAR T cell, iCasM28z, activates, proliferates and displays higher efficacy when administered intrapleurally into the chest cavity. In case of a large tumor burden, the functionally exhausted CAR T cells could be rescued by checkpoint blockade anti-PD1 agent.
“The novelty of our study is that the CAR T cells target the cancer cell-surface protein, mesothelin, which is expressed on the majority of cancer cells, and they are delivered directly to the tumor site using regional delivery techniques,” Adusumilli said. “If this approach is successful, 2 million patients with mesothelin-expressing solid tumors per year in the United States will be eligible for this treatment.”
The iCasM28z is the world’s first fully human CAR and contains a “suicide” switch called Icaspase-9 that could kill itself in the event of an adverse anaphylactic reaction in the patient. The trial consisted of 21 patients of which 40 percent of them had received three or more lines of prior therapy. None of the patients who received CAR T cell therapy showed any evidence of toxicity. A clinical response rate of 72% was registered by a sub cohort of 11 patients who also received cyclophosphamide preconditioning and three doses of anti-PD1 agent in addition to the CAR T cells.
“Combining rationally developed strategies—such as interventional radiology, T cell genetic engineering, and newer immunotherapy agents—has produced encouraging results and provides rationale to further investigate this approach in aggressive, therapy-resistant cancers such as mesothelioma, for which the currently available treatment options are not optimal,” Adusumilli noted.
2) Lymphodepletion Chemotherapy Plus HER2 Targeting CAR T Cell Therapy Proves Effective in Sarcomas
With the existing chemotherapy regimens proving inadequate and leading to toxicity, only a handful of options are available for the treatment of sarcomas in children and adults. At this juncture promising data from an open-label Phase I clinical trial was presented by Shoba A. Navai, MD, Assistant Professor at the Baylor College of Medicine.
The study enrolled 10 pediatric and adult patients with refractory HER2 positive sarcoma who received CAR T cells after lymphodepletion. T cell expansion was observed in 9 patients with a median peak expansion on day 7. One patient with rhabdomyosarcoma had a complete response (CR) for 12 months which then relapsed post 6 months without therapy. When that patient was subsequently re-treated, CR was achieved and maintained for 17 months. Another patient with osteosarcoma metastatic to the lungs has an ongoing CR for 32 months. Three patients had stable disease, and 5 had progressive disease.
“Our study shows that HER2-targeted CAR T cell therapy given in combination with lymphodepletion chemotherapy is safe, and though very early, it shows promising anti-tumor activity in some patients with advanced HER2-positive sarcomas,” Navai said.
Cumulative Data from anti-CD22 CAR T Cell Study Confirms Initial Promise but Displays Novel Toxicities
The results of another trial involving lymphodepletion and CAR T cell therapy combo was presented in the meeting. It is the largest study of CD22 CAR T cell therapy to date and is a cumulative extension (52 patients) of a previously reported first-in-human, first-in-child, trial conducted in 21 subjects with Acute Lymphoblastic Leukemia.
Novel therapies are imperative for patients who relapse or develop resistance to anti-CD19 therapy. The phase I study of anti-CD22 CAR T cells (NCT02315612) recruited patients between the ages of 3-30 years with relapsed/refractory CD22 positive disease who received fludarabine and cyclophosphamide lymphodepletion.
A majority of them responded to the immunotherapy with around 46 patients (88.4%) experiencing Cytokine Release Syndrome (CRS). Some novel toxicities were also noted in this cumulative study. They consisted of 3 cases of capillary leak syndrome, 2 cases of atypical hemolytic uremic syndrome, 8 cases of symptomatic coagulopathy and 18 cases of Hemophagocytic lymphohistiocytosis-like manifestations. Relapse occurred at a median of 6 months post CAR in 23 (64%) subjects primarily due to CD22 modulation.
Overall, the updated trial confirmed the initial efficacy but also highlighted the appearance of novel toxicities. These promising data warrant further testing of this CD22 CAR in a Phase 2 clinical trial.
Updates from the KEYNOTE-189 Study
AACR 2018 witnessed the announcement of outstanding data from the Phase 3 KEYNOTE-189 trial. It featured Merck’s Keytruda (pembrolizumab) which in combination with chemotherapy drug pemetrexed and cisplatin or carboplatin showed significant improvement in the primary endpoints for patients with metastatic NSCLC. The combo treatment registered a superior overall survival of 51% as compared to the placebo with chemotherapy arm. This year, the company presented the results from a post-hoc analysis of patients with liver or brain metastases from the trial
“At this year’s AACR meeting, we are pleased to share important data from our broad clinical development program in lung cancer, as we continue to understand the effects of KEYTRUDA in subsets of patients with advanced lung cancer whose disease has been traditionally difficult to treat,” said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories.
The objective of this analysis was to evaluate outcomes of the combo therapy in patients with liver (16%; n=66) or brain metastases (18%; n=73) at baseline. The results demonstrated that the risk of death was reduced by 38 percent (HR=0.62 [95% CI, 0.39-0.98]) in patients with liver metastases and by 59 percent (HR=0.41 [95% CI, 0.24-0.67]) in patients with brain metastases as compared to chemotherapy alone. Similarly, the PFS was also improved, with a reduction in the risk of progression or death by 48 percent (HR=0.52 [95% CI, 0.34-0.81]) and 58 percent (HR=0.42 [95% CI, 0.27-0.67]) in patients with liver and brain metastases respectively.
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