Lung cancer claims more lives in the United States than any other cancer, but fortunately, Day 3 of AACR18 showed just how much progress has been made in this disease, thanks to immunotherapy.
During Monday’s clinical trials plenary session, talks covering three phase III trials emphasized the benefits of first-line combinations with anti-PD-1/PD-L1 checkpoint immunotherapy—specifically pembrolizumab, atezolizumab, and nivolumab—while another breakthrough study highlighted its impact in the neoadjuvant, or pre-surgical, setting.
Presenting first was NYU Langone’s Leena Gandhi, M.D., Ph.D., who discussed the latest data from Merck’s Keynote-189 trial of pembrolizumab plus chemotherapy (pemetrexed + carboplatin) for patients with metastatic non-small cell lung cancer (NSCLC) lacking EGFR and ALK alterations, two types of genetic mutation seen in a small percentage of lung cancer patients.
While this combination has already been approved by the FDA, these latest results are “practice-changing,” according to Gandhi, who currently leads two CRI Clinical Accelerator lung cancer clinical trials. Compared to chemotherapy alone, immunotherapy plus chemotherapy led to “an improvement in overall response rate, progression-free survival, and overall survival across all groups of patients, irrespective of PD-L1 expression, halving the risk of death, which is an unprecedented effect of therapy in the first-line setting.”
Next, Mark A. Socinski, M.D., of the Florida Hospital Cancer Institute, discussed the results of Genentech’s IMpower150 trial, which involved Ira Mellman, Ph.D., and Daniel Chen, M.D., Ph.D.—two members of CRI’s Cancer Immunotherapy Consortium steering committee—and evaluated atezolizumab in combination with the VEGF-targeting antibody bevacizumab (a drug that inhibits blood vessle formation at tumor sites) and chemotherapy (carboplatin + paclitaxel) in patients with metastatic, non-squamous NSCLC. Like the pembrolizumab study above, patients across the spectrum of PD-L1 expression experienced benefits, albeit only with respect to progression-free survival thus far, although this also encompassed patients whose tumors possessed EGFR and ALK mutations.
The third first-line lung cancer trial—Bristol-Myers Squibb’s CheckMate-227—involved the combination of two immunotherapies, nivolumab and ipilimumab, an anti-CTLA-4 checkpoint immunotherapy, in patients with metastatic or recurrent NSCLC. This combination was tested against standard-of-care platinum-doublet chemotherapy.
While CheckMate-227 didn’t stratify patients by PD-L1 expression, it was the first trial to apply the tumor mutational burden (TMB) biomarker in a pre-specified way. Leveraging insights from their CheckMate-568 trial, BMS employed a cutoff of 10 mutations per DNA megabase, which covers roughly half of all NSCLC patients, and among these patients with high TMB tumors immunotherapy offered a clear benefit.
Overall, almost twice as many patients responded to the immunotherapy combination compared to chemotherapy, and at the one-year mark the proportion of patients whose disease hadn’t progressed was almost three times higher in the immunotherapy-treated group, leading Matthew D. Hellman, M.D., of Memorial Sloan Kettering Cancer Center, who presented the data, to declare that these results “establish the combination of nivolumab plus ipilimumab as a first-line treatment option for patients with high TMB NSCLC.”
In addition to advanced lung cancer, checkpoint immunotherapy can also benefit patients with earlier stage lung cancer, according to preliminary data presented by Johns Hopkins University’s Drew Pardoll, M.D., Ph.D., a co-leader of the CRI-SU2C Cancer Immunology Dream Team as well as a member of the CRI Scientific Advisory Council.
Revealing results from the CRI-funded study that he led, Pardoll highlighted the seemingly incredible impact of anti-PD-1 immunotherapy in patients with stage 1-3 lung cancer. Among 20 patients treated prior to surgery, 9 had “major pathologic responses”—meaning that viable cancer cells made up less than 10% of their resected tumors—and two appeared to have no viable cancer cells, even though in most cases surgery was performed only four weeks after receiving their first dose of nivolumab.
While these major pathologic responses occurred even in tumors with little or no PD-L1 expression, the degree of responses correlated with TMB. Importantly, neoadjuvant immunotherapy did not delay surgical intervention in any of the patients treated, and Pardoll expressed optimism given that “major pathologic response after neoadjuvant chemotherapy in lung cancer is associated with long-term survival.”
Although more time and studies will be necessary to reveal the true potential benefit, thus far immunotherapy appeared to provide significant protection against relapse—after a median follow-up of one year, all but 4 of the 20 patients remained alive and relapse-free, (sadly, one of the four patients died from a traumatic accident unrelated to both cancer and treatment).
This approach is designed to stimulate T cell responses against not only the primary tumor, but also to seek out any other undetectable cancer cells that may have already spread elsewhere. In at least one case, these tumor-targeting T cells were detectable in the patient’s blood a month and a half after surgery.
Pardoll stressed that “while it is still too early to tell whether our findings will translate into lower relapse rate and improved survival, pending confirmation in a larger study, we are very optimistic that this approach will eventually be practice-changing and may augment or even replace chemotherapy prior to surgical resection.”
In a touching moment during his plenary presentation, Pardoll acknowledged the importance of CRI funding, stating, "CRI gave me my first grant ever 30 years ago when I was a struggling assistant professor and had just run out of my dowry money—so thanks to them I'm still standing here 30 years later and am able to give this presentation."
Beyond lung cancer, work led by CRI scientists focused on immunotherapy insights in a number of other cancer types.
The University of Chicago’s Thomas Gajewski, M.D., Ph.D., a member of the CRI Scientific Advisory Council who has received several CRI grants (including a CLIP grant from 2013-2015), highlighted discoveries in melanoma that he made with the help of Stefani Spranger, Ph.D., and Leticia Corrales, Ph.D., two recent CRI postdoctoral fellows in his lab.
With Spranger, Gajewski demonstrated that tumors that express activated b-catenin fail to recruit a specific subset of dendritic cells and thereby are able to prevent “killer” CD8+ T cell infiltration. In mice, even transferring tumor-specific T cells was unable to exert effective anti-tumor activity. In melanoma patients they also recognized an association between secondary recurrence and increased expression of b-catenin as well as a decreased immune signature.
With Corrales, Gajewski demonstrated the important role that bacteria—specifically Bifidobacterium—play in anti-tumor immunity. In mice, they showed that these bacteria enhanced anti-tumor immune responses and made anti-PD-L1 immunotherapy more effective. Furthermore, they recognized that patients who responded to immunotherapy possessed distinct bacteria from those found in non-responders, indicating the value of biomarkers derived from bacterial sequencing. Other experiments with germ-free mice drove home the impact of bacteria on immunotherapy’s effectiveness: it only worked in those mice that received bacterial transplants from responder patients.
Former CRI CLIP Investigator (2015-2017) Nir Hacohen, Ph.D., of the Broad Institute of MIT and Harvard, also sought to identify new predictive markers of immunotherapy response in melanoma patients. Using gene expression, he characterized two T cell states—“exhausted” and “memory”—that were associated with responses to checkpoint immunotherapy.
Another biomarker whose value Hacohen highlighted was TCF7. Simple staining of tumor samples was able to predict patient outcomes based on TCF7 expression, which proved an even more powerful indicator than the total number of CD8+ T cells present, with a connection between higher frequencies of TCF7-expressing CD8+ T cells and positive response to anti-PD-1 immunotherapy.
Rounding out the melanoma talks for Day 3 was the University of Texas MD Anderson’s Stephen Mok, Ph.D., a CRI postdoctoral fellow in the lab of James Allison, Ph.D., a CRI-SU2C Dream Team leader who also serves as the director of the CRI Scientific Advisory Council. Mok discussed how checkpoint immunotherapies targeting the CTLA-4 and PD-1 pathways influence T cell memory against melanoma, and revealed that in combination with GVAX vaccination, anti-CTLA-4 immunotherapy appeared to provide more durable memory than anti-PD-1 treatment.
Additionally, whereas PD-1-induced memory requires CD8 T cells during priming, CTLA-4-induced memory only partially required them. CTLA-4 immunotherapy also led to greater cytokine production during the memory phase and a greater increase in tumor-targeting T cells in the peripheral blood of mice after tumor re-challenge. The durability of this CTLA-4-induced memory was evident in a subsequent experiment that re-challenged mice multiple times, including nearly a year after being treated with the checkpoint immunotherapy antibodies.
Steven Pai, Ph.D., a postdoctoral fellow in the University of California, San Francisco lab of Lawrence Fong, M.D.—a CRI Clinical Team Leader and member of the CRI Clinical Accelerator Leadership—also explored the impact of these two checkpoint immunotherapy approaches. While these treatments have been shown to be effective in certain advanced, high tumor burden disease scenarios, Pai revealed a somewhat counter-intuitive consequence of administering these therapies in cases with low tumor burden, where the combination approach can actually compromise anti-tumor effects. This negative effect appeared to be due to excessive production of interferon gamma (IFNg), which induced apoptosis and led to the deletion of the dominant tumor-specific T cells.
Unlike melanoma, pancreatic cancer is notoriously resistant to checkpoint immunotherapy no matter the tumor burden. One person deeply involved in figuring out how we might sensitize these tumors to immunotherapy is the University of Pennsylvania’s Robert Vonderheide, M.D., D.Phil., a member of both the CRI Scientific Advisory Council and Clinical Accelerator Leadership. In fact, he’s currently leading a CRI Clinical Accelerator trial testing a CD40-based combination immunotherapy in pancreatic cancer, and at AACR18, Hannah Dada, Ph.D., a member of his lab, presented some of their findings regarding how CD40 and radiation therapy can enhance the efficacy of combination checkpoint immunotherapy.
Together, these combined therapies were able to overcome pancreatic cancer’s resistance to immunotherapy through mechanisms that involved both the innate and adaptive immune systems. Specifically, tumor control required the activity of both short-lived myeloid cells as well as CD4+ and CD8+ T cells. However, through studies using knockout mice Dada showed that these responses were independent of canonical immune activation, making it clear that there is still much to uncover regarding the immune landscape of pancreatic cancer.
Even as strategies that combine existing agents are developed to overcome tumor resistance to immunotherapy, other scientists, such as Susan Kaech, Ph.D., are discovering and validating new immune checkpoints that could be targeted to help patients mount successful immune responses against their tumors.
Kaech, the Oliver R. Grace-CRI CLIP Investigator at the Salk Institute, described how metabolic pathways can also function as checkpoint receptors that suppress anti-tumor immune responses. Of particular interest was the CD36 receptor that regulates fatty acid homeostasis in T cells. She noted that tumor-infiltrating T cells express higher levels of CD36 and that this can promote tumor growth and T cell exhaustion and has even been shown to mediate metastasis. Therefore, Kaech decided to “knock out” CD36 in T cells, which led to increased activity in the Akt and mTOR pathways, presumably reversing the metabolic dysfunction associated with CD36 activity. While more work remains to be done to characterize this target and its mechanisms, Kaech’s work thus far shows that strategies to inhibit the CD36 immune checkpoint could potentially enhance the activity of tumor-targeting T cells and ultimately enable stronger anti-tumor immune responses both alone and in combination with existing immunotherapies.
While checkpoint immunotherapies that unleash cancer-fighting T cells thus far haven’t proven very effective against leukemia, these patients have had remarkable responses to cellular immunotherapies that can directly target cancerous blood cells.
Work out of Fred Hutch that was presented by Kelly Paulson, M.D., Ph.D., (and led by Philip Greenberg, M.D., a member of the CRI Scientific Advisory Council who has received several CRI clinical grants) discussed one such cellular immunotherapy involving transgenic T cells with engineered TCRs designed to target the WT1 tumor antigen that is frequently overexpressed in acute myeloid leukemia (AML).
Paulson’s talk focused on one particular AML patient, who achieved a year-long remission after treatment with these WT-1 targeting T cells, but then relapsed despite the fact that the transferred T cells were both present and active. She was especially puzzled to find that the AML cells still expressed the WT1 antigen and that the target epitope sequence was not mutated.
This led her to ask, “If the T cells were active, how did the AML escape?”
Surprisingly, the relapsed AML cells had ceased to express the immune proteasome Beta-1i, through which the WT1 antigen was processed and presented, suggest evidence of possible immunoediting (whereby the tumor cells that—for whatever reason—are able to evade detection by the immune system go on to survive and even thrive). After recognizing this, Paulson and Greenberg engineered new T cells that were able to successfully target the WT1 antigen on the standard proteasome—and destroy the relapsed AML cells.
Subsequent analysis revealed that these immune-evading AML clones were already present in the early stages of the disease, leading Paulson to suggest that future immunotherapy approaches might be made more effective by targeting multiple epitopes as well as administering cellular therapy earlier in the treatment regimen.
Speaking of cellular immunotherapies for blood cancer, one of the more interesting concepts presented thus far at AACR18 involved the development of off-the-shelf CAR T cells for leukemia patients.
The work, which was led by Fate Therapeutics’ Bob Valamehr, Ph.D., and involves Memorial Sloan Kettering’s Michel Sadelain, M.D., Ph.D., a CRI-SU2C Dream Team grantee, used induced pluripotent stem cells (iPSC) to generate CAR T cells that target the CD19 receptor that is found on all B cells, including malignant leukemia and lymphoma cells.
Importantly, these "universal" CAR T cells—called FT819—lack normal T cell receptors, which serves to prevent graft-versus-host disease, a potentially damaging autoimmune response against the patient’s own cells. As a result, claimed Valamehr, they can be “packaged, stored, and made readily available for treatment of a large number of patients.” This would potentially broaden patient accessibility and reduce cost of manufacture and delivery compared to personalized CAR T cellular therapies currently approved for treatment of certain types of lymphoma and leukemia.
The clinical efficacy and safety profile of this universal iPSC CAR T therapy remains to be seen in future clinical trials, however Valamehr showed that, in preclinical studies, the approach resulted in the successful targeting and attack of CD19-positive tumor cells. In addition, it was able to generate antibody-dependent cellular cytotoxicity (ADCC) when combined with a CD20-targeting antibody. Finally, as this CAR T cell lacks a T cell receptor by design, there is a significant reduction in the risk of graft-versus-host disease, a severe and potentially fatal immune system reaction.
Come back tomorrow for our recap of the fourth and final day of AACR18.