Category Archives: AACR

The future of cancer immunotherapy?

Matthew Herper posed a provocative question the other day while discussing CAR T technology: is this how we’ll cure cancer? (link).

Lets look at another example that promises to evoke the same question. Back in April, Steve Rosenberg gave a remarkable talk on the subject of patient-specific tumor-infiltrating-lymphocytes (TILs). We covered this talk in an earlier post (link). Today Dr Rosenberg further exemplified this personalized immunotherapy approach, via a case report in Science (link).

The patient had a highly metastasized gastrointestinal epithelial cell tumor called a cholangiocarcinoma. The patient had been through multiple rounds of chemotherapy, relapsed, and was enrolled in a clinical trial (NCT01174121). Lung metastases were isolated and subjected to whole exome sequencing. At the same time, these tumor samples were processed to derive TILs. The data from the sequencing identified multiple gene (and therefore proteins) that were mutated, and and expression constructs were used to determine if any of the mutated proteins were recognized by the TILs, which would proliferate when stimulated by interaction with antigen. Remarkably, a peptide fragment of the mutated ERRB2IP protein stimulated CD4+ Th1-type T cells in a HLA-restricted manner. These T cells were then expanded ex vivo.

The patient first received an expanded, activated TIL pool containing about 30% CD4+ T cells reactive to the mutated ERRB2IP protein. 40 Billion (yes, ‘B’) T cells were administered along with IL-2, a cytokine that keeps T cells alive and proliferating upon activation. The reactive TILs persisted for many months after administration and impacted the tumor, reducing tumor volume and inducing stable disease (a defined clinical endpoint). Ex vivo stimulation of recovered TILs demonstrated strong expression of the T cell activation receptors 4-1BB and OX40, and the secretion of the cytokines IFN-gamma, TNF and IL-2. The patient maintained tumor regression for 13 months, at which point metastases were observed in the lungs. A second infusion of activated TILs was given. In this case  >95% of the TILs were reactive to the mutated ERB2IP protein. 10 Billion cells were administered. The patient then experienced a tumor regression that was maintain and progressive over time, up to and including 6 months post-administration (the last timepoint provided in the report).

This is an exciting step, moving immunotherapy into a class of tumors that are stubbornly resistant to many immunotherapeutic agents. A few interesting questions arise: 1) would induction of a CD8 response have an additive impact on the tumor? 2) would use of an agonist antibody to OX40 or 4-1BB synergize with this technique? 3) What was the immunosuppressive phenotype of the tumor and metastases, and could this information be exploited in the context of immune checkpoint blockade. 4) How often will metastases reflect the mutational landscape of the parental tumor (or other metastatic clones)? 5) Can the TIL technique be wedded to CAR T technology?  I suppose there are many questions and issues.

This is a great next step in the rapid evolution of oncology treatment, and I’m looking forward to seeing much more.

stay tuned.

Novel Synergies Arising in the Immunotherapy of Melanoma

Steven Rosenberg gave an interesting talk at this year’s American Association for Cancer Research meeting (AACR 2014). He discussed various cell therapies that were developed at the National Cancer Institute (NCI). He began with a review of 3 trials in metastatic melanoma that used the patient’s own tumor infiltrating lymphocytes (TILs), isolated, expanded and re-injected, as the treatment. Ninety-three patients were enrolled in the trials. The partial response rate (PR) was 32% and the complete response rate (CR) was 22%. Notably, some of the CRs were durable; Dr Rosenberg went so far as to state that TIL therapy could be curative, albeit in a relatively low percentage of patients treated. In a new trial of 110 patients they are seeing similar results, including durable PRs.

Similar attempts to use TIL therapy in other solid tumors have mainly failed. So one interesting question, posed by Dr Rosenberg, is why do melanomas readily respond immune therapies? Such therapies include not just TIL-based treatment but also to high-dose IL-2, checkpoint inhibitors: blocking CTLA4, blocking the PD-1 pathway, even agonist anti-CD40 antibody (mAb) treatment. All of these therapies will activate cytotoxic T cells and should also activate the rest of the immune system either secondarily, or in the example of agonist anti-CD40 mAb therapy, directly.

Melanomas are unusual in the abundance of TILs that are found within the tumor and the tumor microenvironment. Rosenberg floated the “mutation” hypothesis to explain why TILs are abundant in melanoma: melanoma tumors are highly mutated, with an average of 34 mutations per individual patient tumor. The mutation hypothesis posits that it is the abundance of mutations and therefore mutated proteins that drive TIL accumulation, that is, the mutations produce antigenic protein fragments that can be presented in context of MHC (MHC class I and class II are complexes found on antigen-presenting cells that activate T cells).

If this hypothesis is correct than several predictions can be made. One is that we should be able to find antigenic peptides that activate the TILs from specific patients. Another is that the TILs should be disabled by the tumor or tumor microenvironment (this is already suggested by the success of immune checkpoint inhibitors like ipilimumab and nivolumab in melanoma). Indeed, TILs isolated from patient melanomas express multiple immune control pathways, both in the immune response inhibitory pathways (PD-1, CTLA4, TIM-3) but also immune response activation pathways (4-1BB, OX-40, CD25, CD28, CD27, CD70) and others (LAG-3). So, these calls appears primed to respond, but are held in check.

Further, the TILs are primed to respond, at least in part, to tumor-derived peptides. Dr Rosenberg and colleagues sequenced the tumors from individual patients and used an algorithm to scan the data and identify immunogenic peptide fragments. They then synthesized the peptides and ask whether any of them could stimulate patient TILs. For each patient they found several immunogenic peptides. They could then isolate the T cell receptor (TCR) that mediated that recognition, and use it in an expression construct to develop mutation specific T cells. Note here that it is the TCR on the T cell that interacts with the MHC complex on antigen-presenting cells to trigger T cell activation. We have moved now from bulk TILs expanded ex vivo and re-injected to patient-specific engineered T cells specific for tumor antigens. This TCR-based cell therapy has now shown activity beyond melanoma and may be useful for other solid tumors that contain large populations of TILs. Finally, it may also be feasible to use the TIL immunogenic peptide data to craft highly tumor specific CAR constructs, i.e. by raising the CAR Vh domain (engineered as a scFV) to tumor-mutated antigens.

There remain significant unanswered questions. Other tumor types carry very high mutational burdens but do not accumulate large numbers of TILs – why not? The expression of immune control pathways on TILs derived from melanomas is complex – how best to manipulate these pathways? Also, how do TIL immune control phenotypes vary among patients? The identification of patient-specific immunogenic peptides may be useful in moving tumor vaccine therapy forward – how best to incorporate this data? Finally, a theme we always return to – how should doctors and patients use TCR-based therapeutics in the context of other available therapies.

The TIL data remind us that tumors raise an immune response to tumors, and this has implications for the re-emerging tumor vaccine field. Perhaps these mutated tumor antigens could be used in the context of tumor vaccination. There were several talks at AACR14 describing successful application of tumor vaccines in early phase clinical trials. There have been high-profile failures in this space – GSK’s phase 3 bust with their MAGE-A3 vaccine being a notable recent example. But sticking to melanoma, we see a few strong signals emerging.

Roger Perlmutter updated results from Amgen’s Phase 3 trial with T-Vec, which was initiated during his tenure (he is now at Merck). The T-Vec program was brought into Amgen with the $1 billion buyout of BioVex. T-Vec is a engineered viral vaccine that can infect and then replicate in tumor cells, pumping out the pleiotropic, immune-system priming growth factor GM-CSF along with encoded antigen. The injection is given at accessible tumor sites, e.g. in the skin, causing the melanoma to shrink. Importantly, not just the injected tumors, but tumors distant from the injection site responded, indicating that a systemic immune response had been triggered. T-Vec was compared to GM-CSF injection alone. While the overall response rate was high (about 60%) the interesting data are the comparisons of duration of response.

 

time to progression or death (primary endpoint)

       overall survival (OS)         (a secondary endpoint)

GM-CSF

2.9 months

19 months

T-Vec

9.2 months

23.3 months

The response can be traced to cytotoxic T cells. These initially resemble patient TILs. However, after immunization these T cells have up-regulated immune response proteins (CD28, CD137, CD27, GITR) and down-regulated immune checkpoint proteins (PD-1, CTLA4, Lag3, TIM-3). So this immunization protocol is resetting the T cell phenotype, from immunosuppressed or anergic, to immune-competent and activated. This biological response is likely driven by the effect of GM-CSF on monocytes, macrophages and related cells. The mechanism of action bears further study.

We have not seen enough data yet to determine if there will be long-term responders (those that contribute to the “long tail” phenomena on OS curves) as we see in the immune checkpoint inhibitor trials. Regardless, Amgen is moving forward with clinical trials of T-Vec in combination with anti-CTLA4 mAb (Vervoytm, from Bristol-Myers Squibb) and with anti-PD-1 mAb MK-3475, in collaboration with Merck.

Lindy Durrant and colleagues from the University of Nottingham used a different approach to engage the immune system in the vaccine setting. They developed SCIB1, a DNA immunotherapy that encodes epitopes from gp100 and TRP-2 (melanoma antigens) into a human IgG1 antibody (honestly I need to understand better how they engineered this). The DNA vaccine is electroporated directly into muscle weekly x 3 and then at 3 months and 6 months. The transfection results in expression of the construct that is then taken up by Fc-receptor bearing cells via the CD64 Fc-receptor. CD64+ cells include monocytes, macrophages, dendritic cells and other immune cells. This Phase 1 study was designed as a 3×3 dose escalation study with an expansion cohort at the maximum tolerated dose, determined to be 4mg. Stage III and Stage IV melanoma patients were enrolled. 19/20 patients were shown to have an immune response to vaccination. There was a clear dose response. In the expansion cohort (n = 14) all patients showed an immune response despite expression of PD-L1 on tumor cells. Epitope recognition by both CD4 and CD8+ T cells was observed. Median survival of the expansion cohort is currently 15 months.

While this is a small early stage trial, such results are dramatic and highlight the concept that productively engaging the immune response requires recruitment of the patient’s antigen presenting cell populations (as noted above in the T-Vec example, this is what GM-CSF does). The tumor cell profile data hint at the potential use of PD-1 pathway blockade as a co-therapy for this DNA vaccine approach.

For smaller companies developing cancer vaccine modalities the potential to develop their technology alongside immunotherapy agents should be attractive. While PD-1 and CTLA4 targeting antibodies remain one obvious approach, data presented at AACR suggest that immune activating pathways (GITR, OX40 and others) might also be useful in the context of immune vaccine approaches. The trick will be to aim carefully.

We’ll follow up with a look at immune activation pathways.

stay tuned.

Three high-altitude take aways from AACR14

The American Association for Cancer Research (AACR) 2014 meeting last week was high energy and high impact. We will dive into particular talks and specific pathways and indications in later posts, in the meantime I wanted to mention a few key themes.

1) Immunotherapy Versus The World.  That’s a deliberate overstatement of a subtle shift in emphasis from last year’s big meetings, where combinations of immunotherapy with just about anything else were the hot topic. This year there were several talks which emphasized the futility of chasing oncogenic pathways and all of their resistance mutations, one after the other, as opposed to letting the immune system do the work. However, it seems to me overly optimistic to believe that immune modulation can defeat a high percentage of patient  tumors on its own, as some speakers acknowledged. Combinations remain necessary although we will have to work past some notable failures in combo trials, such as the liver toxicity seen in the ipilimumab + vemurafenib combination phase 1, discussed briefly by Antonio Ribas               (see http://www.nejm.org/doi/full/10.1056/NEJMc1302338).

2) Immunotherapy Versus Itself.  In the ultimate battle of the titans, we see different immunotherapeutic modalities squaring off. This is a theme we’ve touched on before in this space, but the  competition is getting heated. In some indications, the leukemias, lymphomas, perhaps melanoma and some other solid tumors, there is an abundance of therapeutic choices, and the hard question of which therapy best suits which patient will ultimately need to be addressed outside of the context of clinical trial enrollment. Several talks really brought this message home. Roger Perlmutter of Merck (and before that, Amgen) envisions an important role for multiple immune therapies including bi-specific antibodies, chimeric antigen receptors (CARs), and immune checkpoint modulators like Merck’s anti-PD-1 antibody MK-3475.  For B cell lymphoma for example, there is blintumumab (Amgen), a potent bi-specific that redirects T cells to CD19+ tumor cells (and normal B cells), and there is CTL019, a CAR therapeutic which does much the same thing. The therapeutic profiles and toxicity differ, but the general idea is the same. One big difference is that while CTL019 drives T cell expansion and the development of long term anti-tumor memory, the bi-specific does not. Which is better? We don’t know yet. He did not mention that one might do well trying a course of BTK inhibition plus anti-CD20 antibody therapy, perhaps with restricted chemotherapy first e.g ibrutinib plus rituximab and chemo (R-BR or R-F). That choice comes down to efficacy, then toxicity, and eventually cost. Efficacy seems to be a home run with the CAR therapeutics, although these may run into trouble in the area of toxicity and cost calculation. Renier Brentjens discussed the CAR therapies being developed under the Juno Therapeutics umbrella. Acute lymphoid leukemia (ALL) can be treated with CAR 19-28z modified T cells to achieve a >80% complete response rate with >70% of patients showing no minimal residual disease, an outstanding result. However, 30% of treated patients end up in the ICU due to cytokine release syndrome and other toxicity, and recently patients in the ALL trials have died from unanticipated tox causes. Juno stopped 5 trials of their CAR technology last week due to toxicity. Apparently one patient died of cardiovascular complications and another of CNS complications (severe uncontrolled seizures) – it was hard to nail down as Dr Brentjens had gone off his prepared talk for these remarks which were off the cuff, so comment please if you have better info on this. Carl June discussed Dr Brentjens’ presentation, noting that the clinical results were really quite striking, and contrasting the CD28 motif-based CARs with the 4-1BB-based CARs (as designed by Dr June with U Penn and licensed to Novartis). He also stressed that in chronic lymphocytic leukemia (CLL) they have had patients who have failed up to 10 prior therapies, including rituximab and/or ibrutinib, and these patients have responded to CAR treatment. That’s very impressive data. The roadblocks to widespread use of CAR therapy however are large and include the toxicity, the “boutique” nature of the current protocols, the cost. Perhaps, Dr June suggested, CAR will end up as third line therapy, reserved for salvage therapy. I for one hope not.

Also in the immunotherapy space were hot new targets (e.g. CD47, OX40, GITR), advances on the vaccine front, and a few surprises. We’ll update soon.

3) The Medicinal Chemists Have Been Busy.  Not to be drowned out by the Immunotherapy tidal wave, small molecule therapies targeting specific oncogenic pathways continue to be developed and show promise. Most readers will be aware of the high stakes showdown (so billed) between Novartis, Pfizer and Lilly in the field of specific CDK4/6 inhibitors – in addition to bringing forward some really nice phase 2 data (we’ll discuss these another time) this “showdown” also illustrates that current portfolio strategy drives a lot of overlapping effort by different companies. As expected, much of the action is moving downstream in the signaling pathways, so we saw some data on MEK1 inhibitors and ERK1/2 inhibition. There were some new BTK inhibitors, nice advances in the epigenetics space, and some novel PI3K inhibitors. All grist for the mill.

stay tuned.

Update from AACR14: Clinical Halt for Memorial Sloan Kettering/Juno Therapy in Non-Hodgkin Lymphoma

Yesterday we learned that the Memorial Sloan Kettering Cancer Center (MSKCC) and corporate partner Juno had stopped enrolling patients into 5 clinical trials of their chimeric antigen receptor (CAR) T cell therapies. Details are spare at this point, but unexpectedly, the cause of the clinical stop was severe cytokine release syndrome (CRS). I say ‘unexpectedly’ because it was just last month that MSKCC released an update on their ability to detect CRS early enough to initiate aggressive treatment. We commented on this update in a recent post on the CAR 19-28z technology.

According to the MSKCC update given in February, they had developed “guidelines for managing the side effects of cell therapy” including CRS, and “diagnostic criteria” for identifying at-risk patients using clinical lab tests. These tests were for a panel of cytokines and for C-reactive protein (CRP). To be fair these comments were made in reference to work ongoing in acute lymphocytic leukemia (ALL), but it was clear that the clinicians felt they were broadly applicable. It seems now that these comments were premature.

This is a critical issue in the CAR technology field, potentially holding back not just MSKCC/Juno but similar work from U Penn/Novartis and NCI and partners working with Kite Pharma. The syndrome characterized as CRS is a consequence of the massive immune response to the tumor, which is a designed consequence of the CAR technology. CAR-modified T cells are potent cytotoxic agents, and are designed to recruit unmodified T cells to the cause (the so-called bystander effect). This result is the triggering of the acute phase response, and then an outpouring of cytotoxic compounds, pro-inflammatory cytokines, and effector proteins. When allowed to proceed unchecked, the response begins to engulf normal cells and tissues, causing additional cell death, organ damage, and in the most severe cases, death.

The reality is that clinical responses leading to CRS seem to have caught MSKCC/Juno flat footed in at least one clinical trial of Non-Hodgkin’s Lymphoma (NHL) – we note here that stopping 5 trials does not mean that CRS was seen in all 5, but they are related by clinical indication, so it is an obvious precautionary step to take.

What will happen next we cannot know yet, as we have not yet heard the necessary detail. At the very least the MSKCC/Juno NHL programs are in for careful scrutiny. This will impact the clinical development of the technology and slow access for patients. The patients affected are those who are the most in need, nonetheless, the caution is warranted. More broadly, this unexpected turn of events may encourage us to look again at more established therapeutics for NHL, including small targeted molecule drugs, cytotoxic antibodies, antibody-drug conjugates (ADCs) and bispecifics, and of course, combinations of those therapies with one another or with current chemotherapeutics.

And this just in: In the immune checkpoint space we have just learned this morning of the potential for unexpected immune toxicity after long term treatment. Thankfully this appears to be very rare but this too will bear watching.

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