TAMS, M2 está asociado a la diseminación del cancer, efecto opuesto de M1.
Human breast cancer cells educate macrophages toward the M2 activation status
The immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression
the highest objective response rates observed in cancer types with a high mutational burden such as melanoma and non-small cell lung cancer, likely related to an enriched neoantigen repertoire, However significant limitations exist with these therapeutic agents when used as monotherapy, with objective responses to PD-1 blockade observed in only 30–40% of patients, and the majority of patients demonstrating innate resistance. Acquired resistance to anti-PD-1 therapy is also a problem, with approximately one quarter of responders later demonstrating disease progression.
they identified high-level mutational loss of key genes involved in immunotherapeutic responses, involving defects in antigen presentation and in interferon signalling.
It is, however, becoming increasingly clear that a significant proportion of resistance mechanisms may not be related to genomic events. Functional reprogramming of gene expression is an increasingly-described resistance mechanism in targeted therapies
tumor cell resistance to IFN-γ (JAK2 mutation) or IFN-α/β/γ (JAK1 mutation) despite T cell recognition of tumor antigen
Patients treated with sipuleucel-T (an approved vaccine targeting prostatic acid phosphatase in prostate cancer) demonstrated significant increases in T cells at the periphery of tumor microenvironment when evaluated after resection.11 Greater infiltration within the tumor could have been limited by immune-suppressive components of the tumor microenvironment including PD-L1 expression by the tumor. Nonetheless, these data provide an important proof of concept. Several trials are now underway deploying anti–CTLA-4 and vaccines in combination with PD-1/PD-L1 in an attempt to capitalize on this immune intensification strategy.
Interesante: como podemos hacer un tumor más inmunogénico
The success of anti–PD-1/–PD-L1 therapies may be predicted by immunohistochemistry findings, but that approach misses the bigger opportunity to turn patients whose disease doesn’t respond into patients with disease that responds by initiating immune mobilization to the tumor microenvironment. Future trials should not focus on patient selection but rather on patient optimization through approaches that not only ensure an activated immune response within the tumor but that also facilitate full functionality of those cells within the hostile tumor microenvironment so the spoils of this immunologic revolution can have a broader clinical impact.
Curr Opin Immunol. 2017 Feb 22;45:73-81. doi: 10.1016/j.coi.2017.01.003. [Epub ahead of print]
Targeting NK-cell checkpoints for cancer immunotherapy.
Muntasell A1, Ochoa MC2, Cordeiro L2, Berraondo P1, López-Díaz de Cerio A3, Cabo M1, López-Botet M1, Melero I4.
Natural Killer (NK) cells are cytotoxic lymphocytes specialized in early defense against virus-infected and transformed cells. NK-cell function is regulated by activating and inhibitory surface receptors recognizing their ligands on transformed cells. Modulation of NK numbers and/or function by a variety of agents such as cytokines and monoclonal antibodies may result in enhanced anti-tumor activity. Recombinant cytokines (i.e., IL-15 and IL-2), antibodies blocking inhibitory receptors (i.e., KIR, NKG2A and TIGIT) and agonists delivering signals via CD137, NKG2D and CD16 stand out as the most suitable opportunities. These agents can be used to potentiate NKcell- mediated antibody-dependent cellular cytotoxicity (ADCC) against antibody-coated tumor cells, offering potential for multiple combinatorial immunotherapy strategies against cancer.
, immunotherapy will likely replace our second-line approaches and challenge our front-line therapy standard
Researchers in a phase I trial reported a 76 percent disease control of mesothelioma with Keytruda at the American Association for Cancer Research annual meeting in 2015. Only patients whose tumor cells had at least 1 percent expression of PD-L1 were used.
During the 2016 International Association for the Study of Lung Cancer, researchers in a phase II trial reported a 56 percent disease control rate with Keytruda, even though more than half the patients had no detectable PD-L1 expression.
A third trial, involving Opdivo and no requirement of PD-L1 expression, reported a disease control rate of 50 percent.
In the largest clinical trial for a PD-L1 inhibitor, researchers reported a disease control rate of 56.6 percent using the drug avelumab.
These combinations should be rationally driven rather than randomly selected, he stressed. For example, it is now recognized that tumors have phenotypes ranging from inflamed, with abundant tumor-infiltrating lymphocytes and PD-L1, to a so-called immune desert.2 The former respond to immune checkpoint inhibitors, whereas the latter generally do not but can be made responsive through the use of combinations that convert them to inflamed.
Vacunas y neoantígenos...
Treatment approaches for circumventing immune escape have focused on the two processes required for T-cell activation: antigen presentation to the T cell and co-stimulation involving antigen-presenting cells.
Efforts to enhance antigen presentation with antigen vaccines in lung cancer have been largely negative. “It’s not a bad approach, but we don’t know exactly what the clinically important neoantigens are,” he explained. A related hurdle has been differentiating self-antigens, which are also present on healthy tissues, from neoantigens, which result from patient-specific mutations that lead to unique epitopes.
Pérdida o regulación a la baja de IFNAR1 como mecanismo de resistencia inmune
Protein IFNAR1 Helps Solid Tumors Resist Immunotherapies
Down-regulation of the receptor is required for the generation of immune-privileged niches in the tumor microenvironment,” Fuchs said. “Accordingly, this decreases the efficacy of immune therapies. So, if we can reverse that, then we’ll probably improve the outcome of treatment
Y ahora viene el problema de quien va a financiar todo esto, y el precio de unos meses más de vida. Aunque en realidad, una de las cosas más interesantes es que no produce los daños tan brutales de la quimioterapia (aunque tiene problemas y algunos efectos autoinmunes peligrosos).
NICE echando para atrás Keytruda, al menos con los datos provisionales
NICE said that Keytruda gives on average 29 months of extra life, at least three months more than standard chemotherapy treatment, but could not be sure about these figures because of uncertainties in the data.
The company’s cost-effectiveness estimate, of more than £50,000 per Quality Adjusted Life Year gained, therefore exceeded the range usually considered to be a cost-effective use of NHS resources.
This is despite the fact that NICE allowed extra leeway because it considered Keytruda to be a life-extending, end-of-life treatment.
NICE also said that Keytruda did not, in this case, meet the criteria for reimbursement from the Cancer Drugs Fund, which can pay for drugs for around two years while further data is gathered.
Sistema inmune innato, más adaptativo de lo que creemos. Células NK.
Immunological memory is a hallmark of the adaptive immune system. However, the ability to “remember” and respond more robustly against a second encounter with the same pathogen has been described in organisms lacking T and B cells. Recently, natural killer (NK) cells have been shown to mediate antigen-specific recall responses in several different model systems. Although NK cells do not rearrange the genes encoding their activating receptors, NK cells experience a selective education process during development, undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e. memory cells), and mediate more efficacious secondary responses against previously encountered pathogen
Innate immunity features short-lived cells that respond rapidly and non-specifically against pathogen exposure. Re-encounter with the same pathogen is thought to result in a qualitatively and quantitatively identical response as the first encounter. In contrast, adaptive immunity consists of T and B cells, which respond more slowly, but with high specificity due to somatically rearranged genes that generate an infinitely diverse set of antigen receptors.
NK cells require cytokines of the IL-2 receptor common-gamma chain family, particularly IL-15, for their development, homeostasis, and survival