October 23, 2014

More of Better > More or Less of Worse

In a February 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10, Moffitt Cancer Center's Dr. Amod Sarnaik, M.D. said of the cancer center's Phase 1 feasibility study, result of which later were presented at AACR 2014 and ASCO 2014:
“A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic immune response in patients is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma”... 
...The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response... 
...“We generate large numbers of T-lymphocytes, but we don’t have control over their quality. We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease... {Underlined emphasis is mine}
A potent, long-lived systemic immune response to solid tumor cancers should:
(i) Originate at the tumor sites themselves, 
(ii) Require a broader array of tumor antigens to be released and presented, 
(iii) Require this array to be comprised of pristine, un- or non-denatured antigens (i.e., whole tumor antigens, not antigen fragments,), and 
(iv) Result from the subsequent, more comprehensive, T-cell response.

MD Anderson Cancer Center surgical oncologist and Provectus principal investigator Dr. Merrick Ross, M.D., noted in a recent video, below, while speaking at the setting of ASCO 2014:
"The rapid lysis of the tumor and when the tumor is lysed it does not denature the antigen. So the antigens are expressed in a way where an inflammatory response can occur and therefore antigen presentation probably is up-regulated and enhanced, which could lead to a systemic host response." {My transcription, and underlined emphasis is mine}

The idea is to present as many un-denatured or pristine antigens as possible to dendritic cells ("DCs") and antigen presenting cells ("APCs"). Showing fewer pristine antigens or more denatured ones cannot generate a sustainable, systemic, specific, anti-tumor response. Showing more pristine ones should have the opposite and a much better effect.

Said another way, by a shareholder, blog reader and internist whose patients include those afflicted with cancer:
"Rapid lysosomal-mediated tumor lysis following IL injection of PV-10 uniquely produces pristine, un-denatured antigens that up-regulates antigen presentation to DCs and APCs with a resultant systemic immune response (to paraphrase Merrick Ross). The fidelity of these un-denatured tumor antigens (akin to injecting whole tumor antigens, not antigen fragments, into a patient) is what provokes a very accurate and specific immunological T-cell response that bystander tumors are vulnerable to (presuming they don’t possess too many mutated antigens due to selection pressure from previously therapies)." {My transcription, and underlined emphasis is mine}

Roche's Genentech's Drs. Daniel Chen, M.D, Ph.D. and Ira Mellman, Ph.D.'s Oncology Meets Immunology: The Cancer-Immunity Cycle provides the opportunity to illustrate the interplay between (a) immune checkpoint blockade [Step #7] and (b) the creation, release and presentation of antigens [Steps #1 and 2], and the subsequent priming and activation of the immune system [Step #3]. I write interplay of these steps because they appear to be what industry thus far is focusing on when it considers combination therapies for late stage diseases, and permutations of treatments and therapeutics from each of these steps in an eventual combination.

The illustration below builds on (is revised by me of) Chen & Mellman's Figure 1:
The generation of immunity to cancer is a cyclic process that can be self propagating, leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T cell responses. The cycle is also characterized by inhibitory factors that lead to immune regulatory feedback mechanisms, which can halt the development or limit the immunity. This cycle can be divided into seven major steps, starting with the release of antigens from the cancer cell and ending with the killing of cancer cells. Each step is described above, with the primary cell types involved and the anatomic location of the activity listed. Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes.
Click to enlarge.

Various types of treatments and/or therapeutics in Steps #1, #2 and #3 may create and release antigens ("Antigen Release"), present them to DCs and APCs ("Antigen Presentation"), and prime the body's T-cells ("T-Cell Priming).

See Chen & Mellman's section entitled Initiating Anticancer Immunity: Antigen Release.
Attempts to activate or introduce cancer antigen-specific T cells, as well as stimulate the proliferation of these cells over the last 20 years, have led to mostly no, minimal or modest appreciable anticancer immune responses. The majority of these efforts involved the use of therapeutic vaccines because vaccines can be easy to deploy and have historically represented an approach that has brought enormous medical benefit (reviewed by Palucka and Banchereau, 2013). Yet, cancer vaccines were limited on two accounts. First, until recently, there was a general lack of understanding of how to immunize human patients to achieve potent cytotoxic T cell responses. This limitation reflects continued uncertainties concerning the identities of antigens to use, their mode of delivery, the types of adjuvants required, and the proximal characteristics of the desired T cell response (Palucka and Banchereau, 2013). Second, the presence of the immunostat in the tumor microenvironment may dampen or disable antitumor immune responses before clinically relevant tumor kill can occur. Thus, as long as these negative signals are in place, the prospects for vaccine-based approaches used alone are likely to be limited. {Underlined emphasis is mine}
Therapeutic vaccination is not the only approach to accelerating and expanding the production of T cell immunity. Because anticancer T cells can be produced spontaneously, there is a growing appreciation that the tumor itself represents a type of endogenous vaccine. Accessing the naturally occurring source of cancer-associated antigens avoids problems associated with selection and delivery (Heo et al., 2013, van den Boorn and Hartmann, 2013). This approach is also convenient, but achieving it requires detailed knowledge around whether standard of care chemotherapy or targeted therapies are compatible with immunotherapies. Some therapies are thought to cause tumor cell death in a fashion that promotes immunity (reviewed in Zitvogel et al., 2013). However, it is unclear whether this effect can be accurately predicted and will, in any event, require empirical study. Chemotherapy, radiation therapy, and targeted therapies must also be evaluated for their effects on the immune system. Although it is assumed that many might be antagonistic, there are some reports that others might promote T cell activity (Demaria et al., 2005, Duraiswamy et al., 2013, Hiniker et al., 2012, Ott et al., 2013, Postow et al., 2012, Stagg et al., 2011, Zitvogel et al., 2013). {Underlined emphasis is mine}
See Chen & Mellman's section entitled Presentation, and T Cell Priming.
Another exciting development is that the initial demonstrations that genetically modified autologous T cells could be reinfused into patients to yield substantial clinical benefit, at least in certain B cell malignancies (Grupp et al., 2013; reviewed in Kalos and June, 2013). The most well developed of these is the use of “CARs,” or chimeric antigen receptors, in which a patient’s T cells are transfected with a construct encoding an antibody against a tumor surface antigen (typically CD19) fused to T cell signaling domains (Kochenderfer and Rosenberg, 2013). Similar approaches are under investigation with recombinant T cell receptors (reviewed in Kalos and June, 2013). The procedure avoids the need for immunization and may even overcome mechanisms of immune suppression by overwhelming the system through infusion of large quantities of the modified T cells. This can force the revolution of the Cancer-Immunity Cycle, enhancing the accumulation of stimulatory immune factors, and potentially promotes eventual self-propagation of the cycle. The potential limitations here, which are yet to be fully determined, include whether the approach can be extended to cancers beyond hematologic malignancies, whether the delivery of large numbers of monospecific T cells will cause resistance due to antigenic drift, and whether the toxicity issues already identified can be safely managed. {Underlined emphasis is mine}
See Chen & Mellman's section entitled T Cell Priming and Activation.
Whether tumor antigens are delivered exogenously or are captured and presented by DCs endogenously, another strategy for intervening in the Cancer-Immunity Cycle involves the control of T cell activation. This is the presumed primary mechanism of action of anti-CTLA4 antibodies, such as ipilimumab, which blocks the interaction of the major negative regulator of T cells (CTLA4) with its ligands B7.1 and B7.2 (CD80 and CD86; Qureshi et al., 2011). Thus, during antigen presentation in lymphoid organs (or in the periphery), the expansion of T cell responses is disinhibited, thereby promoting the production of autoreactive T cells, including tumor-specific T cells. The lack of selectivity in T cell expansion combined with the fundamental importance of CTLA4 as a checkpoint may underlie the significant immune-related toxicities seen in patients treated with ipilimumab (Hodi et al., 2010). {Underlined emphasis is mine}
This second illustration below builds on (is revised by me of) Chen & Mellman's Figure 2:
The numerous factors that come into play in the Cancer-Immunity Cycle provide a wide range of potential therapeutic targets. This figure highlights examples of some of the therapies currently under preclinical or clinical evaluation. Key highlights include that vaccines can primarily promote cycle step 2, anti-CTLA4 can primarily promote cycle step 3, and anti-PD-L1 or anti-PD-1 antibodies can primarily promote cycle step 7. Although not developed as immunotherapies, chemotherapy, radiation therapy, and targeted therapies can primarily promote cycle step 1, and inhibitors of VEGF can potentially promote T cell infiltration into tumors—cycle step 5. Abbreviations are as follows: GM-CSF, granulocyte macrophage colony-stimulating factor; CARs, chimeric antigen receptors. {Underlined emphasis is mine}
Click to enlarge.

In the cancer immunity cycle, where certain drugs (based on known and yet to be known factors, notably stimulatory and inhibitory) promote a step (or potentially more than one step), who owns what "real estate" (i.e., who owns what drugs) should be key to understanding the competitive landscape, and where it eventually leads. As the researchers, industry and the FDA combine therapies to address the still unmet needs of late-stage cancer patients, ownership of cancer assets used in whatever combinations may and do work (and thus eventually are approved) translates into sales, profit and return on investment (in R&D).

Step #1: Chemotherapies and radiation therapies likely produce more antigen fragments than whole antigens, but antigens nevertheless. Chemotherapies are commoditized (read: inexpensive, not so profitable, and growing obsolete). Radiation therapy is owned and delivered by physicians. There are numerous targeted therapies owned by various pharmaceutical companies. They may or may not generate whole and/or fragmented antigens, but it seems their owners are worried about the dismantlement of their franchises, as some rush to combine and partner with PD-1 and PD-L1 agents.

Step #2
: These agents presumably facilitate the presentation of the antigens released in Step #1, and include failed (or as yet ineffectively utilized) vaccines, CD40 agent owners (like Genentech-Roche, among others), and not-so-valuable-properties-because-of-widespread-use (read: un-patentable, like INF alpha).

Step #3: There potentially is more real estate here. Already owned includes, notably, Bristol-Myers' approved CTLA-4 agent (ipilimumab), and CD137, OX40 and CD27 agents by Pfizer and Roche, among others.

Step #7: The PD-1 owners include Bristol-Myers (Opdivo) and Merck (Keytruda). The PD-L1 owners include Roche and AstraZeneca. IDO owners include, among others, Incyte (non-exclusive combination study relationships/agreements with AstraZeneca, Bristol-Myers, Merck, and Roche) and NewLink (exclusive, now, to Roche)


Celgene's expansion of its license relationship with Sutro today (building on 2012's initial arrangement), provides Celgene with real estate, and potentially special ones at that. In terms of real estate, while the Big Biotech can access CTLA4, PD-1 and PD-L1 via Sutro, it notably also gets LAG-3 and TIM-3 (the next generation of immune checkpoint inhibitors?).
Click to enlarge.
The illustration below builds on (is revised by me of) Chen & Mellman's Figure 3 (note LAG-3 and TIM-3 inhibitors, alongside PD-1 and PD-L-1):
Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity. Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (“immunostat”) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). Examples of such factors and the primary steps at which they can act are shown. Abbreviations are as follows: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high-mobility group protein B1; TLR, Toll-like receptor; HVEM, herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T-lympocyte antigen-4; PD-L1, programmed death-ligand 1; CXCL/CCL, chemokine motif ligands; LFA1, lymphocyte function-associated antigen-1; ICAM1, intracellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indoleamine 2,3-dioxygenase; TGF, transforming growth factor; BTLA, B- and T-lymphocyte attenuator; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte-activation gene 3 protein; MIC, MHC class I polypeptide-related sequence protein; TIM-3, T cell immunoglobulin domain and mucin domain-3. Although not illustrated, it is important to note that intratumoral T regulatory cells, macrophages, and myeloid-derived suppressor cells are key sources of many of these inhibitory factors.
Click to enlarge.
Additionally, according to FierceBiotech, the real estate is special:
"Sutro's team believes it has devised a much better way to build ADCs--those precise cancer cell-killing constructs made up of a targeting antibody, linker and payload--and bispecifics, teeing up potentially best-in-class products that promise to be more efficiently and consistently manufactured. Using biochemical synthesis, they've hatched a technology that can bypass the current approach to biologics by genetically engineering drugs that are much simpler to make, more akin to small molecules." {Underlined and bold emphasis is mine}
PV-10's effectiveness is attributed to its physical chemistry and small molecule nature.

Moffitt presents pre-clinical (murine model) data about PV-10 in combination with co-inhibitory blockade at SITC 2014 (Provectus' press release on the topic is here). Chen and Mellman note "inhibitors shown in red [in their Figure 3] help keep the process in check and reduce immune activity and/or prevent autoimmunity distinguish between checkpoint," but distinguish between CTLA-4, and PD-1 and PD-L-1:
"Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T cell development and proliferation (step 3). We distinguish these from immune rheostat (“immunostat”) factors, such as PD-L1, can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed (step 7). "
The presentation could explain Moffitt's Dr. Jeff Weber, M.D., Ph.D.'s contention PV-10 may be the perfect immune system primer. What does being the perfect primer mean, and entail?

Provectus recently revised its Fact Sheet to note more work by Moffitt, this time on biomarkers:
What happened to the next cohort of the Phase 1 feasibility study? Of the total enrollment of 15 patients, 8 were reported on at AACR/ASCO 2014. April 2014 article PV-10 decreases melanoma cells in tumours, which followed AACR 2014, noted:
Studies are now underway in an additional seven patients to take biopsies and blood samples at more frequent time intervals after PV-10 injection to elucidate the pathways more clearly.
Moffitt's presentation could discuss whether or not PV-10 promotes steps #4, #5 and/or #6 of the cancer immunity cycle. If so, why and how?
Click to enlarge.

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