The second day of the 2018 International Cancer Immunotherapy Conference (CICON), co-hosted by the Cancer Research Institute (CRI), Association for Cancer Immunotherapy (CIMT), European Academy of Tumor Immunology (EATI), and the American Association for Cancer Research (AACR), was a special one that won’t soon be forgotten by those in attendance.
At around 5:30 a.m. ET, the announcement was made that James P. Allison, Ph.D., had been named a recipient of the 2018 Nobel Prize in Physiology or Medicine. Dr. Allison, of the University of Texas MD Anderson Cancer Center, will receive the award along with Tasuku Honjo, Ph.D., of the University of Kyoto, “for their discovery of cancer therapy by inhibition of negative immune regulation,” according to a press release issued by the Nobel Foundation.
Dr. James P. Allison, 2018 Nobel laureate, and Dr. Padmanee Sharma, his wife and colleague, make their way through a standing ovation at CICON18
Returning from a morning full of press conferences and interviews, including an appearance at the CICON18 press luncheon that day, Allison made a dramatic entrance during the afternoon session, and received a hero’s welcome as he proceeded to the main stage with his wife and colleague, Padmanee Sharma, M.D., Ph.D., at his side and flanked by flashing lights and overjoyed scientists. This honor from the prestigious Nobel Foundation recognizing the potential of immunotherapy to transform treatment of all cancers energizes the entire field and signals a major validation of the work of its scientists. Dr. Allison is director of the CRI Scientific Advisory Council and is a Fellow of the AACR Academy and former member of the AACR Board of Directors.
In the afterglow of the Nobel announcement, Ignacio Melero, M.D., Ph.D., of Universidad de Navarra, University Clinic and CIMA, officially kicked off day two of the conference. Melero’s keynote address focused on two distinct immune pathways: interleukin-8 (IL-8) and CD137, otherwise known as 4-1bb.
Melero began by discussing how the levels of IL-8, which can act upon a variety of immune and non-immune cells, can tell us a lot about tumors, including their size (positive association) and how likely they are to respond to immunotherapy (negative association). This is because the IL-8 produced by tumors can promote angiogenesis, recruit immunosuppressive cells like neutrophils and myeloid-derived suppressor cells (MDSCs), and stimulate epithelial-to-mesenchymal transition, which is a precursor to metastasis. In a pooled analysis of several clinical trials in kidney cancer, melanoma, and lung cancer, it was found that patients with higher baseline concentrations of IL-8 in the blood experienced worse outcomes and lower overall survival after being treated with immunotherapy. Based on these findings, a phase I/IIa clinical trial was recently launched to evaluate the combination of anti-IL-8 and PD-1 immunotherapies in patients who have advanced solid cancers and elevated levels of IL-8 in their blood.
Ignacio Melero, M.D., Ph.D., of Universidad de Navarra, University Clinic and CIMA
Turning to CD137, a member of the tumor necrosis factor (TNF) receptor family, Melero explained that tumor-reactive T cells lacking functional CD137 had dysfunctional mitochondria. However, treatment with a CD137 agonist was able to reinvigorate these T cells and enhance their activity over the long-term by altering the epigenetic patterns of genes related to immune functions. Given the ability of CD137-targeting therapies to enhance “killer” T cell activity, Melero suggested that combining this approach with adoptive cell immunotherapy might be a “perfect marriage.”
SESSION 3: Genetically Engineered T Cells
The first full session of the day disussed adoptive cell immunotherapy, with a particular focus on using genetic engineering techniques to enhance the tumor-killing capabilities of natural immune cells even further. In the context of CAR T cells for blood cancers, James N. Kochenderfer, M.D., of the National Cancer Institute, began by highlighting the success that CD19-targeting chimeric antigen receptor (CAR) T cell immunotherapy has had in diffuse large B cell lymphoma (DLBCL). After noting, however, that neurotoxicity has continued to be a major problem, he discussed the development of CD19-targeting CAR T cells in which the CD28 “hinge” was replaced with one from human CD8α designed to provide a weaker activation signal and minimize inflammatory cytokine production. Among the 20 patients treated with this approach in a clinical trial, 75% responded, with 55% having a complete response, and only one patient experienced high-grade neurotoxicity.
James N. Kochenderfer, M.D., of the National Cancer Institute
Next, Kochenderfer spoke about CAR T cells targeting the B cell maturation antigen (BCMA) in multiple myeloma. While 13 of the 16 patients who received the optimal dose (9 million cells / kg) responded, only four of those responses have lasted more than one year, a significantly lower rate than that seen with CD19-targeting CARs in lymphoma. Wrapping up his talk, Kochenderfer described current efforts to engineer T cells with fully human CARs containing only heavy-chain binding domains against BCMA that were able to eliminate established tumors in mice and are now set to be evaluated in a newly opened clinical trial for patients with multiple myeloma. The hope is that the newer version will be even more effective and result in more durable patient responses.
Stanford University School of Medicine’s Crystal L. Mackall, M.D., spoke next about strategies to engineer exhaustion-resistant CAR T cells. By transducing T cells with tonically-signaling, GD2-targeting CARs equipped with a CD28 co-stimulatory domain, she created a reliable model of “exhaustion in a dish,” which she used to explore the biology behind exhaustion. Through analysis of these cells she found that during the transition to exhaustion there are genome-wide changes in the accessibility of genomic enhancers, and was able to identify the transcription factor motifs whose accessibility changed the most in exhausted cells. Additionally, she observed an increased presence of certain inhibitory complexes that were associated with defective IL-2 signaling. This led her to hypothesize that there was an imbalance between the activating and inhibitory members of these transcriptional factor families that resulted in a deficiency of the activating factors. When she tested that hypothesis, she found that overexpression of those presumably deficient activating factors was able to enhance the anti-tumor activity of CAR T cells against leukemia and osteosarcoma. By lowering the activation threshold, overexpressing these activating factors was also able to enhance the activity of CAR T cells in leukemia with a low antigen density.
Crystal L. Mackall, M.D., of Stanford University School of Medicine
The following speaker was Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute, who showcased his latest efforts in adoptive T cell immunotherapy targeting mutated tumor proteins known as neoantigens. In one trial involving 22 melanoma patients with immunogenic mutations—which comprised only 1.4% of all the mutations found in these tumors—he found that 82% of the patients already had tumor-infiltrating T cells targeting at least one of these mutated neoantigens and 63% had T cells that recognized two or more mutated neoantigens. Similarly, in a trial involving 72 patients with gastrointestinal cancers and another involving 99 patients with a variety of epithelial cancers, the vast majority of patients already had neoantigen-reactive T cells. Notably, all the neoantigens within each trial were unique, with the exception of two patients in each of the latter two trials who shared a mutated KRAS neoantigen, which is commonly mutated in a variety of cancers owing to its ability to “drive” oncogenic progression. One patient even possessed four distinct T cell receptors that all targeted the mutated KRAS neoantigen. Due to its prevalence, his lab has begun building a library of all the mutated KRAS-targeting T cell receptors (TCRs) that they’ve found in patients with metastatic cancer. They’re also building a library of TCRs that target the product of the most commonly mutated gene in cancer, the tumor suppressor gene p53 that is mutated in roughly half of all cancers. After identifying the ten “hot spot” regions in the p53 gene that are most likely to be mutated, he developed a novel method involving tandem minigene constructs incorporated these peptides—that could be used to screen patients to see if they possessed any tumor-infiltrating T cells that targeted these neoantigens. Notably, an exceptionally high fraction—almost half—of these p53 “hot spot” mutations are immunogenic.
Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute
Next, Christine E. Brown, Ph.D., of the City of Hope National Medical Center, discussed CAR T cell immunotherapy strategies in brain cancer. She began with a trial involving patients with recurrent or refractory malignant glioma who were treated with CAR T cells targeting the interleukin-13 receptor α2 (IL13Rα2), which is overexpressed in the majority of high-grade gliomas but is largely absent in normal tissue. Higher expression of IL13Rα2 is also associated with poor patient survival. In one unique case, a patient’s inflamed tumor was completely eliminated after treatment, the first such complete response seen in a solid tumor treated with CAR T cells. However, the patient eventually relapsed and the subsequent treatment resistance was associated with the loss of the IL13R2 antigen as well as a decrease in overall antigen presentation and tumor mutational burden. The relapsed tumor was also more heterogeneous in terms of antigen expression.
Christine E. Brown, Ph.D., of the City of Hope National Medical Center
To address the tumor heterogeneity often seen in resistant tumors, Brown covered multi-targeting CAR T cell strategies to “box in” tumors and prevent them from protecting themselves through antigen escape. This could be accomplished in several ways: with multiple CAR T cell populations, each with a single type of CAR that targets a single antigen; with dual CAR T cells that express two different CARs that target two different antigens; and tandem CAR T cells that possess a single CAR construct capable of targeting multiple antigens. As far as new targets, Brown discussed the preclinical efficacy of CAR T cells equipped with chlorotoxin, a protein found in deathstalker scorpion venom that binds to brain cancer cells but not normal brain cells. Other promising new targets that are or will soon be in the clinic include EphA2, CSPG4, PDPN, and CD133. Lastly, in response to the fact that CAR T cell killing of tumor cells can subsequently induce adaptive resistance via PD-L1 expression, she announced a glioblastoma trial evaluating IL13R2-targeting CAR T cells in combination with PD-1 immunotherapy.
After Brown came Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, who also focused on new directions in CAR T cell immunotherapy. First, he spoke about using the gene editing CRISPR/Cas9 technology to integrate the CAR-encoding sequence into the T cell receptor alpha constant (TRAC) locus, which produced CD19-targeting CAR T cells that enhanced survival in mice compared to conventional CAR T cells. These TRAC-CAR T cells decreased their expression of the CAR upon antigen exposure and were also associated with decreased tonic signaling and exhaustion in mice. They’ll soon be evaluated in the clinic in a trial launching next year.
Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center
Second, Sadelain discussed an approach to modify the potentially excessive activation strength of CAR T cells in order to enhance their persistence. To do so, Sadelain explored the role of the ITAMs (immunoreceptor tyrosine-based activation motifs) that initiate the activation of T cells. After creating variations in which the individual ITAM components were modified, he found one version that was able to enhance CAR T cell persistence as well as promote immune memory that protected against tumor re-challenge in mice. These CAR T cells will soon be evaluated in another clinical trial launching in 2019.
Third, he talked about taking advantage of alternative sources of T cells that could potentially overcome some of the obstacles hindering CAR T cell immunotherapy applications. Specifically, Sadelain spoke about a process that takes T cells from the peripheral blood and turns them into induced pluripotent stem cells (T-iPSCs), which have innate-like properties and lack conventional T cell receptors altogether. When these T-iPSCs were equipped with CD19-targeting TRAC-CARs, they too gained the ability to kill human leukemia cells. Ultimately, this approach could potentially be used to provide a self-renewing source of functionally optimized CAR T cells that could be used in both autologous (patient-derived) and allogeneic (donor) settings. An effort to develop a cGMP manufacturing process to create these cells is now under way.
Philip D. Greenberg, M.D., of the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, next discussed an ongoing clinical trial in which patients with acute myeloid leukemia (AML) who’ve received stem cell transplants are being treated with genetically engineered T cells equipped with WT1-targeting TCRs. Importantly, these donor-derived T cells also possessed natural TCRs that were specific for either Epstein-Barr virus (EBV) or cytomegalovirus (CMV). In the prophylactic arm aimed at preventing relapse in patients in remission, single cell analysis of one patient who has remained in remission for over a year revealed that not only did these engineered T cells persist long-term, but they also appeared remarkably similar to the patient’s natural T cells: only six genes met the criteria for differential expression.
Philip D. Greenberg, M.D., of the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine
Greenberg then discussed a new phase I/II trial in which high-risk AML patients who are in remission post-transplant but still have evidence of minimal residual disease (MRD) are being treated with their own T cells—either naïve, central memory, or EBV-specific—that have been engineered to express WT1-targeting TCRs. This trial is also treating patients whose AML has relapsed. One patient in this arm had a complete response after the first infusion of EBV-specific T cells. Unfortunately, this patient’s disease eventually relapsed despite the fact that the engineered T cells were still present at a high level in the blood. This led Greenberg to ask, “Did T cells play a role in maintaining his long remission, and, if so, why did leukemia relapse in the presence of T cells?” Whereas the engineered T cells had a unique signature reflecting activation during the apparent “remission,” at relapse they were no longer activated and more closely resembled the natural T cells. Further analysis revealed that the relapsed AML cells had significantly decreased expression of genes, including those encoding components of the immune proteasome, which led to impaired antigen presentation of WT1. Additionally, it was determined that the AML clones responsible for this escape had long been present in the patient, thus providing strong evidence of an immunoediting process that was being mediated by these engineered T cells.
In the last portion of his talk, Greenberg highlighted a next-generation strategy devised to help tumor-targeting T cells “cheat death.” Normally, FasL on cancer cells can induce T cell death when it binds to the Fas receptor on their surface. To overcome this, he modified the Fas receptor by replacing its intracellular death-inducing domain with the intracellular portion of the co-stimulatory 4-1bb complex. Now, when FasL binds to the modified Fas receptor on these T cells, instead of death it leads to increased mitochondrial activity, proliferation, and even reduced death signaling, and led to enhanced survival in multiple mouse models of cancer.
Next, Christopher A. Klebanoff, M.D., of Memorial Sloan Kettering Cancer Center, discussed his efforts to enhance the persistence of adoptively transferred T cells by targeting inhibitory signaling pathways within the tumor microenvironment. Given the prevalence of FasL expression in the majority of human cancers, and the enrichment of Fas-expressing T cell subsets in many current cellular immunotherapy products, he, like Greenberg, also addressed the impact of FasL-induced cell death. His strategy involved engineering T cells with Fas dominant-negative receptor (DNR) constructs that were able to outcompete normal Fas signaling complexes and thus protect T cells against a broad range of death-inducing factors. As a result, these Fas DNR T cells had enhanced persistence in both the peripheral blood and tumors of melanoma-bearing mice. Furthermore, central memory-like T cells equipped with Fas DNR also performed better than their unmodified counterparts in terms of controlling tumor growth and enhancing the survival of the mice. Meanwhile, the Fas DNR modification also improved the anti-tumor activity of CD19-targeting CAR T cells in a mouse model of acute lymphoblastic leukemia (ALL). Klebanoff has also begun to confirm these findings in human T cells and has thus far demonstrated that Fas DNR can indeed protect them against FasL-induced cell death, too.
Christopher A. Klebanoff, M.D., of Memorial Sloan Kettering Cancer Center
Rounding out the third session of CICON18 was Clare Y. Slaney, Ph.D., of the Peter MacCallum Cancer Centre (Australia), who presented results on an approach that combined adoptively transferred T cells with vaccination. Specifically, this combination involved dual-specific T cells equipped with both an HER2-targeting CAR and a gp100-targeting TCR (CARaMEL), which were administered along with a gp100-expressing recombinant vaccinia virus (VV-gp100), in mice with HER2-positive breast tumors. Slaney found that both treatments were necessary for therapeutic efficacy, with VV-gp100 working to enhance the infiltration of CARaMEL cells into tumors. The combination was also effective against various other HER2-positive tumors and their metastatic lesions, and resulted in the generation of immune memory that protected the mice against tumor re-challenge. The next step—to test this approach with human T cells—is already under way, with the generation of human CARaMEL T cells. Their ability to secrete IFNγ, to proliferate in the presence of cancer cells, and to kill those cancer cells have also been confirmed.
SESSION 4: Maintenance of Immune Balance: Effects of Targeted & Immune Therapies
Alberto Bardelli, Ph.D., of the University of Turin and Candiolo Cancer Institute (Italy), kicked off session four with a counterintuitive approach that aims to target—and inactivate—cancer cells’ ability to repair their DNA. Discussing a trial involving patients with metastatic colorectal cancer (CRC) who were treated with HER2-targeting antibodies, he showed that even within an individual patient, some lesions can respond while others prove resistant, and pointed to the distinct evolutionary trajectories observed in these cancer cells after treatment. Given the distinct survival benefits that have been associated with patients whose CRC is characterized by deficient DNA mismatch repair (dMMR), Bardelli suggested trying to actively induce that phenomenon. As he put it: “We’ve tried to stop cancer evolution, what happens if we do the opposite?” After suggesting that promoting this genomic evolution in tumors might—paradoxically—be beneficial, he showed that knocking out the DNA repair-associated MLH1 gene in immunocompetent mice enabled them to spontaneously reject both colorectal and pancreatic tumors, and improved their survival. These MLH1-knockout mice were characterized by increased “killer” T cell infiltration into tumors, and also improved the effectiveness of dual PD-1 and CTLA-4 checkpoint immunotherapy. In addition to triggering dynamic neoantigen evolution in mouse models of cancer, human cancer cells with similar DNA repair deficiencies, when implanted into mice, were also associated with a significantly increased frequency of both point and frameshift mutations.
Alberto Bardelli, Ph.D., of the University of Turin and Candiolo Cancer Institute (Italy)
The University of Pennsylvania’s David L. Porter, M.D., spoke next about how CD19-targeting CAR T cell immunotherapy might be improved for chronic lymphocytic leukemia (CLL) patients, who haven’t benefited from this approach as much as those with ALL. While the reasons for this aren’t entirely clear, thus far the best correlate for CAR T cell-induced complete responses in patients is the extent to which these cells expand within patients after administration. In that same vein, T cells from CLL patients often have defects in proliferation that limit their expansion. Therefore, Porter hypothesized that combining CAR T cells with ibrutinib, a standard-of-care treatment in CLL, might be able to overcome this limitation. After this combination’s positive effects were validated in preclinical studies, which included decreased expression of PD-1 on T cells, clinical trials were launched to evaluate the approach in human patients. Thus far, eleven treated patients in one trial have had at least three months of follow-up, and 10/11 patients had no detectable CLL cells in their bone marrow while seven experienced strictly-defined complete responses. In another trial, there was a 74% response rate observed in the nineteen patients who received optimal dosing, and four patients had complete responses. Bardelli summed up these results by declaring that “we may have all the right pieces, now we just need to put them together!”
David L. Porter, M.D., of the University of Pennsylvania
Following Bardelli, Peter Savas, M.B.B.S., a Ph.D. student in the lab of Sherene Loi, M.B.B.S., Ph.D., at the Peter MacCallum Cancer Centre (Australia), discussed our current understanding of the immune microenvironment in breast cancer, and how it might be targeted to improve patient outcomes. He noted that, as in several other cancers, there is a correlation between high levels of T cell infiltration into tumors and improved overall survival in patients with node-positive triple-negative breast cancer (TNBC). In addition to their strong prognostic value in early-stage breast cancer, an increased presence of tumor-infiltrating T cells was also associated with increased rates of pathological complete response in all subtypes of breast cancer patients who’ve been treated with neoadjuvant (pre-surgical) chemotherapy. Based on single cell analysis using RNAseq, Savas revealed that a tissue-resident memory (TRM) T cell gene signature was predictive of increased survival in TNBC patients, and appeared to be a stronger prognostic factor than expression of the “killer” T cell-defining CD8 receptor alone. In addition to the predictive value of baseline TRM T cell signatures in metastatic melanoma patients treated with PD-1 immunotherapy, post-treatment expansion of this population’s signature was also associated patient responsiveness. In his conclusion, he noted that while CD4+ and CD8+ TRM T cells are prevalent in primary breast cancers, there is still significant heterogeneity across tumors in terms of TRM subpopulations. Even so, these distinct profiles could serve as a valuable guide when it comes to developing rational immunotherapy strategies for individual patients.
Peter Savas, M.B.B.S., a Ph.D. student in the lab of Sherene Loi, M.B.B.S., Ph.D., at the Peter MacCallum Cancer Centre (Australia)
Next, Patrick Hwu, M.D., of the University of Texas MD Anderson Cancer Center, highlighted how peptide epitopes that result from RNA-editing can provide targetable antigens against which immune responses can be directed. In short, RNA-editing is a process in which a protein known as ADAR (Adenosine Deaminase Action on RNA) replaces an adenosine molecule in an mRNA transcript with an inosine molecule, resulting in a point mutation that can potentially alter a peptide’s amino acid sequence and provide a “foreign,” targetable neoepitope. Hwu pointed to the recent discovery of five HLA-bound peptides that resulted from RNA-editing in melanoma patients. Two of these five altered peptides involved Cyclin1, which is encoded by CCNI gene. Notably, tumor-infiltrating T cells from melanoma patients were able to recognize this RNA-editing-induced Cyclin1 peptide, but not wild-type Cyclin1 peptides, and were able to selectively kill only those human cancer cells that were pulsed with the mutated Cyclin1. In other experiments, overexpression of the edited—but not wild-type—CCNI gene enhanced T cells’ ability to kill human cancer cells, and T cells specific for the edited Cyclin1 peptide were only able to kill those cancer cells that were transfected with the edited version of the CCNI gene. Conversely, downregulation of the Adar1 gene in wild-type melanoma tumors reduced the ability of T cells to recognize the cancer cells. Thus, Hwu concluded, RNA editing provides another mechanism for the generation of mutated peptides that can be presented in the context of major histocompatibility complex (MHC) molecules, enabling them to serve as antigens that can be recognized and targeted by T cell-mediated adaptive immune responses.
Patrick Hwu, M.D., of the University of Texas MD Anderson Cancer Center
Follwing Hwu was Antony Rosen, M.B.Ch.B., M.D., of the Johns Hopkins University School of Medicine. Rosen’s talk focused on the connection between autoimmune responses associated with rheumatic diseases and desirable immune responses directed against cancer. He first observed an “unusual clinical clustering” regarding the timing between when patients were diagnosed with polymyositis or dermatomyositis and when they were diagnosed with malignant cancer. In other words, patients who developed the two conditions often received both of their diagnoses in relatively close proximity to each other, often within a few years. Due to the specificity of autoimmune responses against these self-antigens, and their strong association with clinical trajectory, Rosen set out to unravel a potential mechanism linking the two conditions. Further evidence supporting a potential link was provided by case reports of patients whose scleroderma improved dramatically after they were treated for cancer, observations that cancer onset often occurred around the same time as the development of scleroderma in patients with autoantibodies against the RNA polymerase III (RNAP3) enzyme, and the discovery of an association between scleroderma and anti-tumor immune responses. Because of this, Rosen believed that the specificity of immune responses would enable the identification of the antigen responsible for both types of immunity. To that end, out of eight patients with both scleroderma and cancer who had autoantibodies against an RNAP3 subunit, six of them possessed abnormalities in the subunit’s corresponding gene. None of the other eight patients with both diseases who were examined had this feature. Based on this as well as the identification of “killer” T cells populations capable of targeting mutated and wild-type antigens associated with RNAP3, Rosen proposed a model whereby mutated, cancer-associated antigens first stimulate an immune response that then subsequently spreads to and targets the wild-type antigen, thus causing scleroderma.
Antony Rosen, M.B.Ch.B., M.D., of the Johns Hopkins University School of Medicine
Rosen’s discussion of autoimmune responses segued nicely into the next talk, which was given by the University of California, San Francisco’s Arabella Young, Ph.D., who presented her efforts to address the off-target toxicity that often occurs in patients treated with immunotherapy. She noted that checkpoint immunotherapy can potentially promote the development of autoimmunity, explaining that the PD-1/PD-L1 signaling pathway plays an important role in protecting pancreatic cells against autoreactive T cells. Utilizing a mouse model of sarcoma, she showed that mice that developed PD-1-induced type 1 diabetes also exhibited improved immune responses against their tumors. Even when it is accompanied by a cure for one’s cancer, diabetes is a steep potential cost of immunotherapy. Therefore, Young sought an approach that could provide the best of both worlds—providing protection against immunotherapy-induced development of diabetes without sacrificing the anti-tumor benefits of PD-1 immunotherapy—and found that equipping mice with a specific variant of the IDD gene accomplished just that.
Arabella Young, Ph.D., of the University of California, San Francisco
Finally, Michelle Krogsgaard, Ph.D., of the New York University School of Medicine, closed out the second day of CICON18 with a talk focusing on overcoming resistance to PD-1 immunotherapy. Based on the concept that this resistance is due to altered T cell signaling that results from the combined actions of PD-1 and other inhibitory receptors working in concert, the aim of her work was to determine how exactly these pathways synergize to impact overall T cell activity. This information would then provide a better understanding of the mechanisms underlying immunotherapy resistance, allow for the identification of pathways that these different inhibitory receptors have in common, and then enable the development of therapies that could restore the full cancer-fighting potential of T cells.
Michelle Krogsgaard, Ph.D., of the New York University School of Medicine
She found that melanoma tumors impair the binding affinity between T cell receptors (TCRs) and major histocompatibility complex (MHC) molecules in a tissue-restricted manner, and that blocking the activity of the PD-1/PD-L1 pathway was able to reverse this and increase the affinity of the TCR-MHC interaction. Under normal conditions, the TCR and PD-1/PD-L1 pathways seem to negatively impact each other’s binding and signaling activity, however, this relationship could be uncoupled upon inhibition of Shp-2, which interacts with the PD-1 receptor complex and contributes to certain aspects of T cell exhaustion. In melanoma patients treated with PD-1 immunotherapy, Krogsgaard identified several patterns with respect to co-expression of inhibitory receptors—including PD-1, BTLA, TIM3, and CD28—that were distinct between responders and non-responders. Additionally, she observed that differential levels of phosphorylated Shp-2 and phosphorylated Y418 were only evident in PD-1-positive cells, and that removal of PD-L1 had no effect on the proliferation of T cells in immunotherapy-resistant patients, whereas it increased the proliferation of T cells in patients who responded to immunotherapy.
That’s it for day two of CICON18. Check back later for our recap of the highlights from day three!
All photos by Arthur Brodsky for the Cancer Research Institute.