Category Archives: Macrogenics

Some ideas from Macrogenics: B7-H3, DARTs, ADCs and more

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Macrogenics is a very interesting company whose next 2 or 3 years will surely determine its’ future. And it’s probably about time, as the company has 14 years under its belt. The company is public and trades on NASDAQ as MGNX.

We’ve watched many companies approach a critical time horizon, when possible futures begin appearing. Some companies become great, others wither away, but it is no longer possible to tread water. Macrogenics knows this well, and they are aggressively working to carve a successful path forward. CEO Scott Koenig and CFO James Karrels rang me up the other day, spending about an hour giving me a look under the hood. Our discussion was part history lesson, part update and all very interesting. What follows is just my personal opinion about what we discussed. I’ve tried to place my thoughts in the larger context of the antibody and immunotherapy landscape in the treatment of cancer.

The Macrogenics’ story includes an enhanced Fc technology for cytotoxic antibodies, a bi-specific antibody technology known as DART (see below), a series of partnerships with pharmaceutical companies, and some new initiatives. I’m not going to discuss the past type 1 diabetes effort and the teplizumab antibody as that story is well known.

Lets start with a very interesting program that has been built around the HER2 enhanced Fc antibody, margetuximab. Results from the Phase 1 trial were presented at ASCO last year, and there were early signs of therapeutic activity. The early data showed activity at doses ranging from 1-6 mg/kg qw and 10 mg/kg q3w. This is in the dose range already used for Herceptintm (trastuzumab; 4mg/kg qw or 8mg/kg q3w) and Kadcylatm (trastuzumab emtansine; 3.6 mg/kg q3w). Macrogenics’ hopes that margetuximab can eliminate cancer cells expressing lower levels of Her2 than tumors addressable by trastuzumab (which targets Her2 high expressing cancer cells). Program success hinges on this hypothesis.

Macrogenics is aggressively moving this antibody into Phase 2 and 3 programs including breast, bladder and gastroesophageal cancers with relatively low expression of Her2. The planned phase 3 trial of margetuximab plus chemotherapy in gastroesophageal cancer should start by the end of this year. A phase 2a trial in metastatic breast cancer should wrap up in the second half of this year, and we should see data in 2015. This is important because in the absence of compelling clinical data it will remain difficult for this program to drive further valuation. This is because the Her2 space is very crowded, and it may be hard to establish differentiation and gain leverage. The broad attack against diverse cancer types therefore makes sense. So while I like this program it is going to require compelling phase 2 data to really generate buzz.

The other day I wrote about immune-checkpoint programs         (http://www.sugarconebiotech.com/?p=522) and in this area Macrogenics has nicely positioned its Fc-enhanced anti-B7-H3 antibody MGA-271. This first-in-class program is optioned to Servier, and has advanced to Phase 1 in solid tumors. The company was lucky to pick up this antibody target when it acquired Raven. It is one of a number of B7 family proteins with ill-defined biology. Importantly, Macrogenics focused on the expression pattern of this protein, that is, they treated it as a cell surface target and not as a biology target. This turned out to be a smart move, as this protein is highly and preferentially expressed on a wide variety of tumor cells, and Macrogenics is going after this antigen with a cytotoxic antibody. This type of immune targeting antibody is well positioned for combination with other therapies that “unleash” immune cell responses, particularly the NK cell and macrophage release strategies. We talked about a few of these last week (http://www.sugarconebiotech.com/?p=524). This program looks very interesting and has nothing but upside assuming we do not see a toxicity signal as the clinical trials move forward.

Macrogenics is smartly building out this space. Scott and Jim explained that some of the money recently raised in their stock offering is going to support best-in-class antibody process and manufacturing, and that this will include antibody-drug-conjugates (ADCs), which are toxin payloaded antibodies. Importantly, DARTs directed to appropriate targets will internalize – a prequisite for good ADC-mediated cell death. I asked them if they had chosen a partner for the ADC work (like Seattle Genetics or Immunogen) and they hedged just a bit, saying that different linker-payload combinations might be employed for different antibodies and targets. That’s certainly a reasonable approach, if heavy on the downstream process and formulation steps, so we’ll see what they decide.

An important part of the Macrogenics portfolio is certainly the DART technology. DART is an acronym of Dual Affinity ReTargeting (or Redirected T-cell), depending on the compound. So, there are a couple of different plays here. One is a T cell engagement technology. The furthest developed technology in this class is Micromet/Amgen’s Bi-specific T-cell Engager (BiTE). The CD3 x CD19 BiTE, blinatumamab, recruits T-cells through CD3 and directs them to kill CD19 positive cancer cells. Blinatumamab is reportedly active at concentrations of 100pg/ml or less and certainly in some leukemia settings induces very impressive and durable therapeutic responses, although the side effect profile includes CNS toxicity, including encephalopathy. We will talk much more about the BiTE technology in the next post.

I asked Scott and Jim about the encephalopathy toxicity, specifically whether this is a class effect due to T cell activation. Scott pointed to the way Micromet BiTEs are constructed, and the “floppiness” of the two arms, suggesting that this could have a different impact on a responding T cell than the covalently “locked” DART construct. A second point is that this could be a toxicity that is only seen with the CD19 x CD3 bi-specific and not other bi-specifics. Scott mentioned that similar toxicity has been seen in the setting of CAR-T CD19-directed therapy (CAR19). Honestly, we can’t really judge at this point and will have to await clinical results before we actually know the efficacy/toxicity profiles of various T cell recruitment and activation technologies will compare.

Preclinically, Macrogenics has done a nice job of differentiating itself from BiTEs. In an in vitro study comparing CD19 x CD3 bi-specific formats using the DART technology and the BiTE technology the DART compound was active at much lower concentrations, including against patient derived chronic lymphocytic leukemia cells       (http://bloodjournal.hematologylibrary.org/content/117/17/4403.full). This may not matter so much just yet, as Macrogenics has chosen different bi-specific pairings, and for the moment will not compete directly with the CD3 x CD19 modalities, whether blinatumamab or CAR19.

Macrogenics DART technology has been validated in the partnership space. Boehringer Ingelheim (BI), Servier, Pfizer, and Gilead have all bought into the DART story with partnership deals. BI signed for up to 10 targets across diverse therapeutic areas and modalities and recently choose a DART compound to advance into preclinical development. Pfizer also signed a DART technology deal in 2010 for two cancer targets. Most recently, Gilead acquired rights to four pre-clinical DART programs for cancer indications. Gilead will fully fund research activities for all four programs and will receive global rights to three of the programs. Servier has rights to three DART programs and recently exercised an option to develop the MGD006 DART molecule in development for hematologic malignancies. This antibody is bispecific for CD123 (expressed on leukemias and lymphomas) and CD3 (expressed on T cells). Pre-clinical studies showed that the compound killed CD123-expressing leukemia cells at very low concentrations. A Phase 1 study in relapsed and refractory acute myeloid leukemia will start in the second quarter of 2014. This is the first study of a DART in the clinic.

So while this falls short of actual clinical success, the fact that diverse companies have lined up here is promising. Additional deals should be expected. Macrogenics also mentioned that they have an NK cell retargeting platform as well (one that would compete with the BiKE platform) and it will be interesting to see if deals are made on this technology as well.

Lets take a closer look at the DART targets.

The T cell engagement targets are CD123 (for MGD006) a target on acute myeloid leukemia (AML) cells, and gpA33 (for MGD007) a target on colorectal cancer cells. CD123 expression on AML is a target for ADCS, Bi-specific technologies, and CAR-T technology (CART123). So, this is an important target to understand.

CD123, a subunit of the IL-3 receptor, is over-expressed on AML tumor cells (and other hematopoietic tumor types). It is also expressed on normal hematopoietic stem cells, at a somewhat lower level. Recently, cancer stem cells (CSC) have been highlighted as sources of resistance to therapy. These are stem-like tumor cells that are very resistant to chemotherapy or irradiation, and are hypothesized to be a component of relapse in various tumor types. AML CSC are CD123 positive. Ideally then, therapeutics targeting CD123 will deplete AML tumor cells, deplete AML CSCs and hopefully not deplete normal cells. Because of the uniqueness of the CSC hypothesis, agents targeting CD123 and other CSC markers have gotten a lot of attention.

Lets start with CART123. Just a quick reminder, with CAR-T we are talking about the transduction of patient T cells with a modified TCR, a CD3 subunit and the 4-1BB signaling domain. Very nice preclinical data were presented at ASH last year by the group at The Children’s Hospital of Philadelphia         (https://ash.confex.com/ash/2013/webprogram/Paper60937.html) using technology that has been licensed to Novartis. However, there has been no further news on this target. Very recently, a second CAR-T/CD123 program was described by investigators in Italy and the UK (http://www.nature.com/leu/journal/vaop/ncurrent/abs/leu201462a.html). The preclinical data were compelling, and there did not seem to be an effect on normal cells. We’ll have much more on CAR-T technologies in a separate post.

Further along are competing anti-CD123 antibodies. Xencor developed two anti-CD123 antibodies that were then licensed to CSL limited. The first, CSL360, failed to show signs of clinical activity in a Phase 1 AML trial. The second, CSL362, had excellent cytotoxic activity in preclinical models and a Phase 1 trial in AML is recruiting. In December of 2013, CSL Limited licensed this program to Janssen/Johnson&Johnson. So, this program now has some real muscle behind it. An interesting note on the trial, it is being run in patients currently in remission. If I think this through I think this means the therapeutic hypothesis is two-fold. One, to drive the leukemia to MRD status (minimal residual disease = below the limit of detection); two, to eliminate CD123+ CSCs.

Stemline (NASDAQ: STML) has brought an anti-CD123-ADC antibody into the clinic. They had several presentations at ASH last year, including a phase 1 trial in Blastic Plasmacytoid Dendritic Cell Neoplasm, a rare cancer with high expression of CD123. They showed 5/5 patients responded, with 4/5 having a complete                     response (https://ash.confex.com/ash/2013/webprogram/Paper64672.html). This will be an interesting therapeutic to watch.

Macrogenics presented preclinical data on MGD006 at ASH         (https://ash.confex.com/ash/2013/webprogram/Paper55959.html).  As mentioned above the phase 1 study in AML will start later this year. A second CD123 x CD3 bispecific is being developed by the Cancer Research Institute at Scott & White Healthcare in Texas (they already have an IL-3 fusion protein). There is also a tri-specific targeting CD33, CD123 and CD16 (to activate NK cells). This has made it to the clinic (http://www.translational-medicine.com/content/11/1/289).

Gpa33 is an antigen that is highly overexpressed on colon cancer. This antigen was targeted a few years ago using a humanized anti-gpa33 monoclonal antibody. However the humanization effort did not work well and the therapeutic was highly immunogenic. As far as I can tell Macrogenics is alone in this space.

An earlier stage bi-specific technology at Macrogenics targets multiple antigens. Their CD32 x CD79 bispecific cross links these receptors on B cells and stops cell activation.

As discussed above much of the effort ongoing at Macrogenics is directed to their many partnerships. We do not know the targets for most of these, but one can imagine the direction that Gilead might take, or perhaps Pfizer. The deal with Servier is very interesting in the context of the Servier CAR-T technology deal. As reported in mid-February Servier will collaborate with Paris-based Cellectis on UCART19, an engineered T cell with a chimeric antigen receptor targeting CD19, plus 5 other programs all in leukemia and lymphoma. The company plans to develop combination therapies with immunotherapeutic monoclonal antibodies, small molecules, etc.

What we are seeing then is the co-development of bi-specific modalities directed to the same targets as CAR-T modalities, sometimes by the same company. This latter point is critical and fascinating. Could DARTs and BiTES compete not only with ADCs but also the CAR-T technologies? I don’t know, but we may find out in just a few more years. And we do have to be patient – Macrogenics has no clinical news scheduled until 2015. One way the company could make a splash is if it were to do something big on the corporate side – a buyout, merger, acquisition. Certainly their promotional deck (link here: http://bit.ly/1qpPQWL) makes the point on the last slides that Macrogenics is flexible as it has plenty of capital.

I really like this company – their technology is gutsy and innovative and I wish them the best. Now it’s time for clinical execution: the data will guide us from there. In the meantime there are a few really interesting ways to think about the technology opportunity and the underlying equity value.

cheers, and stay tuned for some thoughts about BiTEs, BiKEs, CARTs and KITEs.

Immune checkpoint inhibitors – Part 2

In part 1 our focus was primarily on the PD-1 and CTLA4 pathways, where the biology is well understood and the drug development advanced. See that post here. In part 2 we look at drug development for some newer immune checkpoint targets, and this will drive us a little deeper into the scientific rationale for some of the less known pathways.

 I would argue that a good deal of the excitement around some recent deals (Novartis/CoStim and Agenus/4-Antibody) really is driven by the opportunity to get in early with novel targets. While the CoStim portfolio included PD-1 pathway related IP, I think the fact that this deal was so early stage suggests that novel LAG-3 and TIM-3 IP had a lot to do with driving interest. Similarly, emerging details from the BIOCIO conference indicate that Agenus (NASDAQ: AGEN), a somewhat obscure company, acquired novel LAG-3, TIM-3, OX40 and GITR antibodies as well as novel CTLA4 and PD-1 antibodies in its’ 4-Antibody acquisition. It would seem that this company, nominally a cancer vaccine company, is taking a huge leap forward by acquiring assets that could be combined with cancer vaccines. Barron’s labeled this a “genius move”, and I agree. This should make Agenus itself an attractive acquisition candidate. The Smith On Stocks Blog has much more on this (http://bit.ly/1ljmEzx).

 So I think it make sense to take on these targets one by one, do a quick update on the therapeutic rationale, and see who is leading the pack. Later we’ll fold this into a landscape analysis to try to understand where the large companies are heading.

We can start with a few targets that are represented by drugs in clinical development. Bristol-Myers Squib (NYSE: BMY), already loaded with anti-CTLA4 and anti-PD-1 programs, is moving their LAG-3 antibody ahead in both monotherapy and combination therapy trials. LAG-3 (lymphocyte activation gene, CD223) is a negative regulator of cell activation. It is expressed on various activated lymphoid cells, including T cells and NK cells that mediate tumor cell killing. The mechanism of action is the binding of LAG-3 to the MHC Class II complex expressed on antigen-presenting cells (B cells, monocytes, macrophages, dendritic cells, and other cell types). The high affinity binding event blocks cell proliferation and effector functions. LAG-3 is also an important mediator of the immune suppressive function of regulatory T cells. Of tremendous interest is the finding that LAG-3 is synergistic with other down-regulatory pathways, specifically PD-1 and TIM-3. As we will see this is driving much of the work on the design of combination therapy testing.

BMS-986016 is an anti-LAG-3 antibody from BMY currently in phase 1 testing in solid tumors and in B cell lymphomas. A very interesting study is NCT01968109: Safety Study of Anti-LAG-3 With and Without Anti-PD-1 in the Treatment of Solid Tumors. This is a Phase 1 dose escalation study of BMS-986016 alone or in combination of one of two defined doses of nivolumab (anti-PD-1). The primary endpoint is safety (AEs, SAEs, fatalities, lab abnormalities). There is also a cardiovascular risk assessment (QTc interval) among the secondary endpoints. Otherwise the secondary endpoints cover PK and exposure, immunogenicity, and RECIST defined tumor responses.

The point is that this is an instructive example of rational combination immunotherapy being investigated at Phase 1.

Other LAG-3 antibodies of potential use in oncology include Immutep’s IMP701, an antagonist antibody. IMP701 ought not to be confused with their depleting anti-LAG-3 antibody IMP731 (partnered with GSK for treatment of autoimmune disease) nor with their activating LAG-3-Fc fusion protein IMP321 (and how this thing works I have no idea). We have already mentioned that CoStim and 4-Antibody had LAG-3 programs and IP, but these would be preclinical. Somewhat better known for its’ anti-CD70 mAb (see below), arGEN-X also lists TIM-3, LAG-3 and VISTA antibodies in its’ preclinical portfolio. No doubt there are other early stage programs, they just are not readily visible yet. I wager that we will see many more of these popping up in the poster aisles at AACR and ASCO this year.

Two proteins related to PD-L1, B7-H3 and B7-H4, are also T cell inhibitory ligands. Both proteins are expressed on tumor cells and expression of B7-H3 or B7-H4 correlates with poor outcome for some tumor types. Both B7-H3 and B7-H4 are normally expressed on myeloid lineage cells including monocytes and dendritic cells. Preclinical tumor model data have supported efficacy with blocking antibodies to these ligands in vivo. The mechanism of action of these ligands is not well understood, as the receptors are not known, or at least cannot be confirmed across different laboratories

The Macrogenics (NASDAQ: MGNX) antibody to B7-H3 has reached clinical development. The phase 1 study in patients with advanced carcinoma, melanoma, or glioblastoma that overexpresses B7-H3. The antibody, MGA271, is licensed to Servier; Macrogenics recently received a milestone payment indicating that the expansion part of the Phase 1 trial had been initiated. Five Prime recently disclosed novel antibodies to B7-H3 and B7-H4 along with TIM-3 and VISTA, as mentioned previously.

With TIM-3 we have a landscape that is a bit earlier than LAG-3 – the excitement about this pathway is driven by the preclinical tumor model data and the translational medicine data. Like LAG-3, TIM-3 has been identified as co-expressed with PD-1, in particular on tumor infiltrating lymphocytes. Genetic data (knockout, transgenic, etc) clearly indicate that TIM-3 is an important immunoregulatory pathway. This is true as well of CTLA4, PD-1 and LAG-3 – the number of “brakes” on the system is remarkable and hints at how dangerous the immune system can be when it is unregulated, as it is in autoimmune, inflammatory, allergic and similar diseases. One of the interesting observations about TIM-3 is that it is ectopically expressed by some tumors and also by dendritic cells associated with tumors, i.e. within the tumor microenvironment. Therefore by blocking TIM-3 in the tumor setting, multiple responses may contribute to efficacy. A confounding issue in the TIM-3 field is the identification of the relevant ligand for TIM-3, with a number of ligands having been proposed (galectin-9, phosphatidylserine (PS), HMGB1). The binding motif for PS is well defined, while binding to the other proposed ligands is less well understood. In particular, TIM-3 and galectin-9 activities seem distinct, at least as far as we can understand from the published genetic data.

The proteins mentioned so far (CTLA4, CD28, CD80, CD86, PD-1, PD-L1, PD-L2, B7-H3, B7-H4, LAG-3, TIM-3, VISTA and TIGIT) are all members of the immunoglobulin (Ig) superfamily of proteins. Two additional protein families of critical importance in regulating immune responses are the TNF and TNF receptor families. Again the leader in this field, clinically at least, is BMY. The antibody BMS-663513 (urelumab) is an agonist anti-4-1BB antibody that functions by stimulating T cell activation. 4-1BB (CD137) is best known for contributing a signaling moiety to the CAR-T constructs (a discussion for another day). BMS-663513 is now in phase 1/2 testing in lymphoma patients. The antibody had previously completed a phase 2 study in melanoma, but that program was put on clinical hold following dose dependent liver toxicity. The new studies utilize lower doses, as a very low dose appears to be efficacious. An important differentiating feature of anti-4-1BB is the apparent ability to eradicate established tumors, at least in some patients. With this is mind it is encouraging to look forward to combination treatment studies. Pfizer also has an anti-4-1BB antibody in development, PF-05082566. This antibody is in a very interesting phase 1 clinical trial in solid tumors and B cell lymphomas, the latter patients being treated with and without rituximab co-therapy.

4-1BB biology is well understood, and agonist stimulation of this receptor induces CD8+ T cell activation, interferon gamma secretion, secretion of cytolytic compounds and recruitment of helper T cells. Of interest, 4-1BB is only expressed on T cells that have been activated through the T cell receptor and CD28, and so is specifically expressed on those T cells that would potentially have anti-tumor activity.

CD27 expression is also induced upon T cell activation, and the critical role of this receptor in immune responses is shown by patients who lack function CD27, as these patients are grossly immunosuppressed. The role of CD27 is subtly different from 4-1BB in that this receptor seems critical to activated T cell survival. Celldex (NASDAQ: CLDX) has developed an agonist anti-CD27 antibody, CDX-1127. In pre-clinical models, CDX-1127 had anti-tumor effects due to enhanced T cell activation. In addition various cancers, particularly B and T cell lymphomas, can express CD27 at high levels and the antibody may be able to such tumor cells directly and activate immune cell killing. Early data is promising, with no obvious toxicities.

The ligand for CD27 is CD70. Paradoxically (and stretching the limits of our understanding of these systems) CD70 is expressed at very high levels on a variety of tumor types, including solid tumors and hematopoietic cancers. Therefore, antibodies targeting CD70 to effect tumor cell killing have been developed. The most advanced of these are antibody drug conjugates, e.g. SGN-75 (SGEN) and MDX-1203 (BMY); there are other coming e.g. from Ambrx. In January. arGEN-X started a Phase 1b expansion study with ARGX-110, a novel cytotoxic anti-CD70 antibody. There are undoubtedly other antibodies in development.

A critical pathway found on cells that interact with T cells (dendritic cells, macrophages, B cells) is the CD40 pathway. Although early work is in the monotherapy setting, it is reasonable to speculate that agonists to CD40 would complement other approaches, such as cancer vaccines and modulators of T cell responses. Dacetuzumab, developed by Seattle Genetics (SGEN) was discontinued in phase 2b. The reason was unclear but appeared to involve both toxicity and futility analysis. Toxicities included cytokine release syndrome (common) and thrombosis (< 5% of patients), some liver toxicity and cytopenias. Most of these toxicities could be controlled with prophylactic agents. CP-870,893 (Pfizer) has completed Phase 1 clinical trials in melanoma, pancreatic cancer and other solid tumors. The current development in the US of CP-870,893 seems limited to trials being sponsored by U Penn’s Abramson Cancer Center. Of note, one of these trials is in combination with the anti-CTLA4 mAb, tremelimumab. The antagonist anti-CD40 antibody lucatumumab (NVS) competed a phase 1 trial in refractory follicular lymphoma in May of 2012. Here the hypothesis was that the bound antibody would activate cytotoxic killing of CD40+ tumor cells. This Phase 1 trial was in combination with chemotherapy (bendamustine).

At this point I would characterize the development of CD40 modulators in oncology as stalled, and awaiting a better understanding of the best antibody activity (and associated isotype) to use, the appropriate dose, and the most relevant tumor types.

Two final pathways to mention in this section are the OX40 and GITR pathways, the subject of headlines when Agenus bought out 4-Antibody. Several clinical stage therapeutics have been developed for these targets.

OX-40 (CD134) is another T cell survival pathway, activated downstream of CD28, and essential for the induction of anti-apoptotic proteins that keep activated T cells alive and functional. It may also be required for the establishment of the memory T cell pool. Stimulation of OX40 by the OX40-L or by agonist anti-OX40 antibodies enhances T cell responses.

AZN/Medimmune has developed a murine anti-OX40 agonist antibody designed to stimulate the immune system and block tumor suppression of the immune response. AZN’s OX40 collaborations are complex. AZN/Medimmune has partnered with AgonOx, a tech transfer spinoff from the Providence Cancer Center in Portland, OR. There are several clinical trials of anti-OX40 therapy underway at the Providence Cancer Center. AZN/Medimmune has also partnered with the Cancer Research Institute and Ludwig Institute for Cancer Research specifically to undertake clinical trials evaluating immunotherapy combinations including the MedImmune antibodies to OX40, and PD-L1 (MED14736), together with other agents within the CRI/Ludwig portfolio and the Cancer Vaccine Collaborative network of clinical immunologists and oncologists. There was one clinical trial co-sponsored by AgonOx and the Ludwig Institute, to study anti-OX40 in combination with ipilimumab. However, this trial has been suspended. According to AZN/Medimmune, the partnership trials are designed to complement their in-house clinical development effort.

GlaxoSmithKline (NYSE: GSK) gained rights to an OX40 antibody preclinical program from the MD Anderson Cancer Center’s Institute for Applied Cancer Sciences, as part of a deal focused on immune checkpoint antibodies that can trigger immune responses against cancer.

GITR was the other target grabbing headlines in light of the Agenus/4-Antibody deal. GITR is yet another cell surface receptor that is involved in amplifying T cell responses. It’s mechanism of action is distinct, in that GITR inhibits the suppressive activity of T-regulatory cells, thereby releasing effector T cells from active suppression. Secondarily GITR signaling is a pro-survival pathway for activated T cells.

GITR, Inc., is a biotech company spun out when Tolerx went under. The company is developing TRX518, an anti-GITR agonist antibody designed to enhance the immune response to cancer cells. A Phase 1 clinical trial in melanoma and solid tumors is currently recruiting after being released from clinical hold.

A few thoughts about these newer pathways. One is that some of them are very potent indeed (4-1BB, CD27) and we will have to watch carefully for toxicity issues. A second is that we can begin to outline rational combinations based on the biology of the pathways. For example, the CTLA4 and PD-1 antagonists may pair well with treatments that induce tumor cell death, thereby releasing novel tumor antigens that the newly stimulated immune system can then recognized. Some of the downstream T cell or antigen-presenting cell activators (CD40, OX40 as examples) may be better suited for use with cancer vaccine therapies.

There are two more classes of immune checkpoint modulators to consider. One consists of the IDO inhibitors. The second consists of the innate immune response modulators (TLRs, KIR, NKG2A). There are very exciting companies working in these areas, and these will be the subject of the next update.

as always please leave a comment or email me at rennertp@sugarconebiotech.com and follow @PDRennert

stay tuned.