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UCLA researchers receive grant to study combination therapy for lung cancer
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Researchers at UCLA received $12 million to conduct a study of pembrolizumab in combination with patients’ genetically modified immune cells for treatment of advanced lung cancer.
Steven M. Dubinett, MD, chief of the division of pulmonary and critical care medicine at UCLA David Geffen School of Medicine and a member of Jonsson Comprehensive Cancer Center and UCLA Broad Stem Cell Research Center, and colleagues will initiate the clinical trial.
Clinicians will draw blood cells from each patient, and researchers will propagate dendritic cells from blood monocytes to genetically modify them with CCL21, a molecule that attracts T cells to tumors.
HemOnc Today spoke with Dubinett about the challenges associated with manipulating tumors in this way, the expectations and timeline for this study, and the potential complications associated with this type of combination therapy.
Question: Can you provide some background about the need for new or more effective therapies for this patient population?
Answer: Although there have been remarkable responses to immune checkpoint inhibitors in lung cancer, the majority of patients still do not respond. A number of factors contribute to this. One of them may be related to failure of antigen presentation at the tumor site. We have been studying this with the goal of fostering systemic immune responses by manipulating the local tumor environment. We have focused on studying the immune suppressive environment in non-small cell lung cancer and especially what’s generated at the tumor site, which fights against and limits the immune responses. At UCLA, one of the primary focuses of my laboratory has been understanding why patients with lung cancer don’t respond to immunotherapy. This research has led us to anticipate that we may be able to manipulate the local tumor environment so that it replicates the lymph node environment and, thus, generates systemic immune responses. More recent studies have shown that, when dendritic cells and lymphoid structures are present at the lung cancer site, those patients tend to have a better prognosis.
Q: Can you explain the role of CCL21 in the study?
A: Tertiary lymphoid structures at the tumor site portend a good outcome. To create that lymph node environment at the tumor site, we introduced the gene for CCL21. This is a chemokine at the entryway of normal lymph nodes. It is responsible for directing mature dendritic cells and lymphocytes into the lymph node. One way to generate a chemokine gradient that would attract dendritic cells and lymphocytes is to have autologous dendritic cells carry CCL21 into the tumor site. We initially studied this in murine models, both testing CCL21 as well cytokines and chemokines such as granulocyte macrophage colony-stimulating factor, interleukin-12, interleukin-7 and others. In particular, CCL21 in preclinical models had a potent systemic antitumor response. We injected one tumor in the mouse and generated systemic antitumor immune responses. When a tumor was injected intratumorally, noninjected contralateral tumors showed resolution. Based on that modeling, we received FDA and Recombinant DNA Advisory Committee approval to do a phase 1 study that was published last year in Clinical Cancer Research. In that study, we found that approximately one-quarter of patients had systemic immune responses to their own tumor antigens. We saw lymphocyte infiltration into the tumor that hadn’t been there previously. At the end of therapy for those patients, PD-L1 was up-regulated at the tumor site.
Based on those studies, we conducted other preclinical work to determine that blocking the PD-1/PD-L1 pathway together with dendritic cells injected into the tumor could engender more lymphocyte activity. There was recognition of tumor antigens, as well as upregulation of PD-L1 and lymphocyte infiltration. The logical next step is the study funded by the California Institute of Regenerative Medicine to assess the combination of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) with dendritic cells expressing CCL21. We refer to this as in situ vaccination because we are actually allowing the autologous dendritic cells to present dominant epitopes in the patient’s tumor. We do not necessarily need to know the patient’s important neoepitopes prior to the therapy. The idea is that healthy dendritic cells that are injected take up antigen in the context of an enriched environment of CCL21, present that antigen to host T cells and, as a result of that CCL21 gradient, attract more endogenous dendritic cells and T lymphocytes to the tumor site.
Q: Could you talk about the study design, population and methods?
A: In the clinical study under the direction of my UCLA colleagues in thoracic oncology — Edward Garon, MD, and Aaron Lisberg, MD — patients will be those receiving first-line therapy for metastatic disease. We plan to enroll patients with low tumor PD-L1 expression, defined as less than 50%. This is a patient group that generally has had a response rate of less than 15% with pembrolizumab alone. Those patients will receive three intratumoral injections of autologous dendritic cells separated by 3 weeks. They will receive concurrent pembrolizumab therapy for a year. The study includes a phase 1 dose escalation in which patients will receive a fixed dose of pembrolizumab but will have increasing amounts of dendritic cells. This will be followed by an expansion cohort in which patients will receive the dendritic cells at the maximum tolerated dose in the context of combination therapy.
Q: How many patients will you enroll?
A: We’re anticipating enrolling 24 to 30 patients.
Q: How many will you need to reach the target for a sufficient response rate?
A: If we have 16 evaluable patients, we would have greater than 80% power to detect a 27% difference in overall response rate.
Q: What is the study timeline?
A: We anticipate a 2- to 3-year enrollment period.
Q: What are the potential implications if this approach is proven safe and effective?
A: If it can be shown that adding in situ dendritic cell therapy to checkpoint inhibitor therapy is safe and effective, there would be additional studies in NSCLC and, potentially, other malignancies. In NSCLC, there also is a significant need for therapies to follow checkpoint inhibitor resistance. The revolution in cellular therapies, the increasing awareness of the importance of antigen presentation, and the groundbreaking results from checkpoint inhibitor therapies combine to create avenues for rationally determined combination therapies that could significantly improve patient outcomes. – by Rob Volansky
For more information:
Steven M. Dubinett, MD, can be reached at David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., CHS 37-131, Los Angeles, CA 90095; email: sdubinett@mednet.ucla.edu.
Disclosure: Dubinett reports scientific advisory board roles with AstraZeneca, EarlyDx and T-Cure.